Benzo(5,6)cycloheptapyridines, compositions and methods of use

ABSTRACT

Derivatives of benzo[5,6]cyclohepta pyridine, and pharmaceutically acceptable salts and solvates thereof are disclosed, which possess anti-allergic and anti-inflammatory activity. Methods for preparing and using the compounds are also described.

The present application is a continuation of U.S. application Ser. No.07/816,777 now abandoned, filed Jan. 2, 1992, which is a division ofU.S. application Ser. No. 345,604, filed May 1, 1989 (now U.S. Pat. No.5,089,496), which is a continuation-in-part of U.S. application Ser. No.181,860, filed Apr. 15, 1988, now abandoned which in turn is acontinuation-in-part of U.S. application Ser. No. 925,342, filed Oct.31, 1986 (now U.S. Pat. No. 4,826,853); and the benefits of theseapplication is claimed under 35 U.S.C. 120.

The present invention relates to benzo[5,6]cyclohepta pyridines and topharmaceutical compositions and methods of using such compounds.

U.S. Pat. Nos. 3,326,924, 3,717,647 and 4,282,233, European publishedApplication No. 0042544 and Villani et al., Journal of MedicinalChemistry, Vol. 15, No. 7, pp 750-754 (1972) and Arzn. Forch 361311-1314 (1986) describe certain11-(4-piperidylidene)-5H-benzo[5,6]cyclohepta [1,2-b]pyridines asantihistamines. U.S. Pat. No. 4,355,036 describes certain N-substitutedpiperidylidene compounds.

The invention in its chemical compound aspect is a compound having thestructural formula I: ##STR1## or a pharmaceutically acceptable salt orsolvate thereof, wherein: one of a, b, c and d represents N or NR⁹ whereR⁹ is O⁻, --CH₃ or --(CH₂)_(n) CO₂ H where n is 1 to 3, and theremaining a, b, c and d groups are CH, which remaining a, b, c and dgroups optionally may be substituted with R¹ or R² ;

R¹ and R² may be the same or different and each independently representshalo, --CF₃, --OR¹⁰, --COR¹⁰ --SR¹⁰, --N(R¹⁰)₂, --NO₂, --OC(O)R¹⁰, --CO₂R¹⁰, --OCO₂ R¹¹, alkynyl, alkenyl or alkyl, which alkyl or alkenyl groupmay be substituted with halo, --OR¹¹ or --CO₂ ;

R³ and R⁴ may be the same or different and each independently representsH, any of the substituents of R¹ and R² R³ R⁴, or and together mayrepresent a saturated or unsaturated C₅ -C₇ ring fused to the benzenering;

R⁵, R⁶, R⁷ and R⁸ each independently represent H, --CF₃, --COR¹⁰, --CO₂R¹⁰, alkyl or aryl, which alkyl or aryl may be substituted with --OR¹⁰,--SR¹⁰, --N(R¹⁰)₂, --NO₂, COR¹⁰, OCOR¹⁰, OCO₂ R¹¹, CO₂ R¹⁰, OPO₃ R¹⁰ orone of R⁵, R⁶, R⁷, and R⁸ may be taken in combination with R as definedbelow to represent --(CH₂)_(r) -- where r is 1 to 4 which may besubstituted with lower alkyl, lower alkoxy, --CF₃ or aryl or R⁵ may becombined with R⁶ to represent ═O or ═S, and R⁷ may be combined with R⁸to represent ═O or ═S;

R¹⁰ represents H, alkyl or aryl;

R¹¹ represents alkyl or aryl;

X represents N or C;

when X represents C, an optional double bond to carbon atom 11 may bepresent;

the dotted line between carbon atoms 5 and 6 represents an optionaldouble bond, such that when a double bond is present, A and Bindependently represent H, --R¹⁰, --OR¹⁰ or --OC(O)R¹⁰, and when nodouble bond is present between carbon atoms 5 and 6, A and B eachindependently represent H₂, --(OR¹⁰)₂, H and halo, dihalo, alkyl and H,(alkyl)₂, --H and --OC(O)R¹⁰, H and --OR¹⁰, ═O, aryl and H, ═NOR¹⁰ or--O--(CH₂)_(p) --O-- where p is 2, 3 or 4 and R¹⁰ is as previouslydefined;

Z represents O, S, ═NR¹³ or H₂ with R¹³ representing R¹⁰ or --CN suchthat

(a) when Z is O or NR¹³, R may be taken in combination with R⁵, R⁶, R⁷or R⁸ as defined above, or R represents H, aryl, alkyl, --SR¹¹,--N(R¹⁰)₂, cycloalkyl, alkenyl, alkynyl or --D wherein --D representsheterocycloalkyl, ##STR2## wherein R³ and R⁴ are as previously definedand W is O, S or NR¹⁰ wherein R¹⁰ is as defined above,

said cycloalkyl, alkyl, alkenyl and alkynyl being optionally substitutedwith from 1-3 groups selected from halo, --CON(R¹⁰)₂, aryl, --CO₂ R¹⁰,--OR¹², --SR¹², --N(R¹⁰)₂, --N(R¹⁰)CO₂ R¹⁰, --COR¹², --NO₂ or D, wherein--D and R¹⁰ are as defined above and R¹² represents R¹⁰, --(CH₂)_(m)OR¹⁰ or --(CH₂)_(q) CO₂ R¹⁰ wherein R¹⁰ is as previously defined, m is 1to 4 and q is 0 to 4,

said alkenyl and alkynyl R groups not containing --OH, --SH or --N(R¹⁰)₂on a carbon containing a double or triple bond respectively;

(b) when Z represents S, R represents in addition to those R groupsabove, aryloxy or alkoxy; and

(c) when Z represents H₂, R represents --COOR¹⁰, --E--COOR¹⁰ or--E--OR¹² where E is alkanediyl which may be substituted with aryl--OR¹⁰, --SR¹⁰, --N(R¹⁰)₂ or --D where D, R¹⁰ and R¹² are as previouslydefined.

In a preferred embodiment of the invention, Z represents O or S, and Rrepresents alkyl, cycloalkyl, alkenyl, aryl or alkyl substituted with--OR¹², --SR¹², --N(R¹⁰)₂ or --COR¹². More preferably, when Z representsO or S, R represents alkyl having from 1 to 3 carbon atoms, or alkyl offrom 1 to 3 carbon atoms substituted with --OR¹², --SR¹², --N(R¹⁰)₂, orCOR¹². Preferably one or both of R³ and R⁴ is halo, e.g. chloro orfluoro. The most preferred value of R³ and/or R⁴ is a halogen located atcarbon atom 8 and/or 9, as shown in the following numbered ringstructure: ##STR3## The nitrogen preferably is located at position "a".R⁵, R⁶, R⁷, R⁸, A and B preferably are H. X preferably is a single ordouble bonded carbon. The bond between positions 5 and 6 preferably is asingle bond. The bond between the piperidyl ring and the cycloheptylring preferably is a double bond.

Preferably when Z is H₂, R is --E--COOR¹⁰ or --E--OR¹².

Compounds of the invention include:

11-(1-acetyl-4-piperidylidene)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine;

11-(1-methoxyacetyl-4-piperidylidene)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine;

11-(1-benzoyl-4-piperidylidene)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine;

11-[1-(3-chlorophenylacetyl)-4-piperidylidene]-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine;

11-[1-(3,4-dimethoxybenzoyl)-4-piperidylidene]-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine;

8-chloro-11-(1-acetyl-4-piperidylidene)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine;

8-chloro-11-(1-propionyl-4-piperidylidene)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine;

8-chloro-11-(1-trimethylacetyl-4-piperidylidene)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine;

8-chloro-11-[1-(t-butylacetyl)-4-piperidylidene]-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine;

8-chloro-11-(1-methoxyacetyl-4-piperidylidene)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine;

8-chloro-11-[1-(ethoxyacetyl)-4-piperidylidene]-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine;

8-chloro-11-[1-(2-hydroxypropioyl)-4-piperidylidene]-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine;

9-chloro-11-(1-methoxyacetyl-4-piperidylidene)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine;

8-chloro-11-[1-(2-methoxypropioyl)-4piperidylidene]-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine;

8-chloro-11-[1-(2-oxopropioyl)-4-piperidylidene]-6,11-dihydro-5H-benzo[5,6]-cyclohepta[1,2-b]pyridine;

8-chloro-11-[1-(1-ethoxycarbonylmethyl)-4-piperidylidene]6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine;

8-chloro-11-[1-(t-butoxycarbonylaminoacetyl)-4-piperidylidene]-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine;

8-chloro-11-(1-trifluoroacetyl-4-piperidylidene)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine;

8-chloro-11-(1-benzoyl-4-piperidylidene)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine;

8-chloro-11-[1-(3,4,5-trimethoxybenzoyl)-4-piperidylidene]-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine;

8-fluoro-11-(1-acetyl-4-piperidylidene)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine;

8-fluoro-11-(1-n-butyryl-4-piperidylidene)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine;

8-fluoro-11-(1-methoxyacetyl-4-piperidylidene)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine;

9-fluoro-11-(1-acetyl-4-piperidylidene)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine;

9-fluoro-11-(1-methoxyacetyl-4-piperidylidene)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine;

3-methyl-8-chloro-11-(1-acetyl-4-piperidylidene)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine;

8,9-difluoro-11-(1-methoxyacetyl-4-piperidylidene)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine;

8-methyl-11-(1-methoxyacetyl-4-piperidylidene)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine;

8-chloro-11-(1-cyclopropylcarbonyl-4-piperidylidene)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine;

8-chloro-11-(1-n-butyryl-4-piperidylidene)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine;

8-methoxy-11-(1-acetyl-4-piperidylidene)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine;

9-chloro-11-(1-acetyl-4-piperidylidene)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine;

8,9-difluoro-11-(1-acetyl-4-piperidylidene)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine;

8-methyl-11-(1-acetyl-4-piperidylidene)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine;

8,9-dichloro-11-(1-acetyl-4-piperidylidene)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine;

8-chloro-11-[1-(2-(2-hydroxyethoxy)ethyl)-4piperidylidene]-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine;

8-chloro-11-[1-[4-(4-t-butylphenyl)-4-hydroxybutyl]-4-piperidylidene]-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine;

8-chloro-11-(1-ethoxydicarbonyl-4-piperidylidene)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine;

8-chloro-11-(1-aminoacetyl-4-piperidylidene)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine;

8-chloro-11-(1-formyl-4-piperidylidene)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine;

8-chloro-11-(1-thiobenzoyl-4-piperidylidene)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine;

8-chloro-11-[1-thioethoxycarbonyl-4-piperidylidene]-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine;

8-chloro-11-[1-thioacetyl-4-piperidylidene]-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine;

8-bromo-11-[1-acetyl-4-piperidylidene]-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine;

8-chloro-11-(1-acetyl-4-piperidylidene)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridineN-oxide;

8-chloro-11-(1-acetyl-4-piperidylidene)-11H-benzo[5,6]cyclohepta[1,2-b]pyridine;

8-chloro-11-(1-acetyl-4-piperazinyl)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine;

8-chloro-11-(1-methylaminocarbonyl-4-piperidylidene)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine;

13-(1-acetyl-4-piperidylidene)6,13-dihydro-5H-naphtho[2',3':5,6]cyclohepta[1,2-b]pyridine;

8-chloro-11-[1-acryloyl-4-piperidylidene]-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine;

8-chloro-11-[1-(2-methoxy-2-methylpropionyl)-4-piperidylidene]-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine;

1-methyl-8-chloro-11-(1-acetyl-4-piperidylidene)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridiniumiodide;

8-chloro-11-[1-acetyl-4-piperidinyl]-11H-benzo[5,6]cyclohepta[1,2-b]pyridine;

5-hydroxy-8-chloro-11-(1-acetyl-4-piperidylidene)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine;

8-chloro-11-[1-dichloroacetyl-4-piperidylidene]-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine;

5-methyl-8-chloro-11-[1-acetyl-4-piperidylidene]-5H-benzo[5,6]cyclohepta[1,2-b]pyridine;

3-methyl-8-chloro-11-[1-acetyl-4-piperidylidene]-5H-benzo[5,6]cyclohepta[1,2-b]pyridine;

8-chloro-11-[1-acetyl-4-piperidylidene]-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridin-5-one;

5-methyl-8-chloro-(1-acetyl-4-piperazinyl)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine;

8-chloro-11-[1-acetyl-2-methyl-4-piperazinyl]-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine;

8-chloro-11-[1-acetyl-(E)-2,6-dimethyl-4-piperidylidene]-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine;

8-chloro-11-[1-acetyl-(Z)-2,6-dimethyl-4-piperidylidene]-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine;

8-chloro-11-[1-acetyl-2,6-dimethyl-4-piperazinyl]-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine;

8-chloro-11-(1-methoxyacetyl-4-piperazinyl)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine;

8,9-difluoro-11-(1-acetyl-4-piperidylidene)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine-N-oxide;

8-chloro-11-(1-formyl-4-piperazinyl)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine;

8-chloro-11-(1-acetyl-4-piperidyl)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-c]pyridine;

2-[8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-yl]hexahydropyrrolo[1,2-a]pyrazin-6(2H)-one;

11-[1-(aminocarbonyl)-4-piperidylidene-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-c]pyridine;and

3,8-dichloro-11-(1-acetyl-4-piperidylidene)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine.

Particularly preferred compounds include:

8-chloro-11-(1-acetyl-4-piperidylidene)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine;

8-chloro-11-(1-methoxyacetyl-4-piperidylidene)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine;

8-chloro-11-(1-propionyl-4-piperidylidene)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine;

8-fluoro-11-(1-acetyl-4-piperidylidene)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine;

9-fluoro-11-(1-acetyl-4-piperidylidene)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine;

8-bromo-11-[1-acetyl-4-piperidylidene]-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine;

8,9-difluoro-11-(1-acetyl-4-piperidylidene)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine;

11-(1-acetyl-4-piperidyl)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine;

3,8-dichloro-11-(1-acetyl-4-piperidylidene)-6,11-dihydro5H-benzo[5,6]cyclohepta[1,2-b]pyridine;

3-methyl-8-chloro-11-(1-acetyl-4-piperidylidene)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine;

8-chloro-11-(1-acetyl-4-piperazinyl)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine;and

8-chloro-11-(1-acetyl-4-piperidylidene)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridineN-oxide.

The invention also is directed at a process for producing a compoundhaving structural formula I wherein the substituents are as previouslydefined by:

a) reacting a compound of formula II with a compound of formula III,wherein L represents a suitable leaving group ##STR4##

b) direct conversion of an N-alkyl compound of formula V with a compoundof formula III ##STR5##

or, c) cyclization of a compound of formula XII ##STR6##

The invention also is directed at a compound of the formula XII ##STR7##wherein the substituents have the same definitions as in formula I.

The invention also encompasses a pharmaceutical composition whichcomprises a compound of formula I as defined above in combination with apharmaceutically acceptable carrier.

The invention further encompasses a method of treating allergy orinflammation in a mammal, comprising administering a compound of formulaI to said mammal in an amount effective to treat allergy orinflammation, respectively.

The invention also comprises a method for making a pharmaceuticalcomposition comprising mixing a compound of formula I with apharmaceutically acceptable carrier.

As used herein, the following terms are used as defined below unlessotherwise indicated:

alkyl--(including the alkyl portions of alkoxy, alkylamino anddialkylamino)--represents straight and branched carbon chains andcontains from one to twenty carbon atoms, preferably one to six carbonatoms;

alkanediyl--represents a divalent, straight or branched hydrocarbonchain having from 1 to 20 carbon atoms, preferably 1 to 6 carbon atoms,the two available bonds being from the same or different carbon atomsthereof, e.g., methylene, ethylene, ethylidene, --CH₂ CH₂ CH₂ --, --CH₂CHCH₃, --CHCH₂ CH₃, etc.

cycloalkyl--represents saturated carbocyclic rings branched orunbranched of from 3 to 20 carbon atoms, preferably 3 to 7 carbon atoms;

heterocycloalkyl--represents a saturated, branched or unbranchedcarbocylic ring containing from 3 to 15 carbon atoms, preferably from 4to 6 carbon atoms, which carbocyclic ring is interrupted by 1 to 3hetero groups selected from --O--, --S-- or --NR¹⁰ -- (suitableheterocycloalkyl groups including 2- or 3-tetrahydrofuranyl, 2- or3-tetrahydrothienyl, 2-, 3- or 4-piperidinyl, 2- or 3-pyrrolidinyl, 2-or 3-piperizinyl, 2- or 4-dioxanyl, etc.);

alkenyl--represents straight and branched carbon chains having at leastone carbon to carbon double bond and containing from 2 to 12 carbonatoms, preferably from 3 to 6 carbon atoms;

alkynyl--represents straight and branched carbon chains having at leastone carbon to carbon triple bond and containing from 2 to 12 carbonatoms, preferably from 2 to 6 carbon atoms;

aryl (including the aryl portion of aryloxy)--represents a carbocyclicgroup containing from 6 to 15 carbon atoms and having at least onearomatic ring (e.g., aryl is a phenyl ring), with all availablesubstitutable carbon atoms of the carbocyclic group being intended aspossible points of attachment, said carbocyclic group being optionallysubstituted with one or more of halo, alkyl, hydroxy, alkoxy, phenoxy,CF₃, amino, alkylamino, dialkylamino, --COOR¹⁰ or --NO₂ ; and

halo--represents fluoro, chloro, bromo and iodo.

Certain compounds of the invention may exist in different isomeric aswell as conformational forms. The invention contemplates all suchisomers both in pure form and in admixture, including racemic mixtures.

The compounds of the invention of formula I can exist in unsolvated aswell as solvated forms, including hydrated forms, e.g., hemihydrate. Ingeneral, the solvated forms, with pharmaceutically acceptable solventssuch as water, ethanol and the like are equivalent to the unsolvatedforms for purposes of the invention.

As noted above, the pyridine and benzene ring structures of formula Imay contain one or more substituents R¹, R², R³ and R⁴. Similarly, theheterocyclic ring D may contain one or more of R³ and R⁴. In compoundswhere there is more than one such substituent, they may be the same ordifferent. Thus compounds having combinations of such substituents arewithin the scope of the invention. Also, the lines drawn into the ringsfrom the R¹, R², R³ and R⁴ groups indicate that such groups may beattached at any of the available positions. For example, the R¹ and R²groups may be attached at the 1, 2, 3 or 4 positions while the R³ and R⁴groups may be attached at any of the 7, 8, 9 or 10 positions.

R⁵, R⁶, R⁷ and R⁸ are attached to the piperidylidene or piperazine ring.As such they may be the same or different The variables R⁵ and R⁶, inaddition to representing H, may represent variables attached to the sameor different carbon atoms in said ring. For example, when R⁵ and R⁶ arecombined to represent ═O or ═S, they are attached to the same carbonatom. Similarly, R⁷ and R⁸ may be attached to the same carbon atom, suchas when R⁷ and R⁸ together represent ═O or ═S. Also, one of R⁵, R⁶, R⁷and R⁸ may be taken in combination with R to represent an alkylenechain, --(CH₂)_(r) --, where r is 1 to 4, thereby forming a fused ringwhich contains a nitrogen.

Certain compounds of the invention will be acidic in nature, e.g. thosecompounds which possess a carboxyl or phenolic hydroxyl group. Thesecompounds may form pharmaceutically acceptable salts. Examples of suchsalts may include sodium, potassium, calcium, aluminum, gold and silversalts. Also contemplated are salts formed with pharmaceuticallyacceptable amines such as ammonia, alkyl amines, hydroxyalkylamines,N-methylglucamine and the like.

Certain basic compounds of the invention also form pharmaceuticallyacceptable salts, e.g., acid addition salts and quaternary ammoniumsalts. For example, the pyrido- or pyrazino- nitrogen atoms may formsalts with strong acid, while compounds having basic substituents suchas amino groups also form salts with weaker acids. Examples of suitableacids for salt formation are hydrochloric, sulfuric, phosphoric, acetic,citric, oxalic, malonic, salicylic, malic, fumaric, succinic, ascorbic,maleic, methanesulfonic and other mineral and carboxylic acids wellknown to those in the art. The salts are prepared by contacting the freebase form with a sufficient amount of the desired acid to produce a saltin the conventional manner. The free base forms may be regenerated bytreating the salt with a suitable dilute aqueous base solution such asdilute aqueous sodium hydroxide, potassium carbonate, ammonia and sodiumbicarbonate. The quaternary ammonium salts are prepared by conventionalmethods, e.g., by reaction of a tertiary amino group in a compound offormula I with a quaternizing compound such as an alkyl iodide, etc. Thefree base forms differ from their respective salt forms somewhat incertain physical properties, such as solubility in polar solvents, butthe salts are otherwise equivalent to their respective free base formsfor purposes of the invention.

All such acid, base and quaternary salts are intended to bepharmaceutically acceptable salts within the scope of the invention andall acid and base salts are considered equivalent to the free forms ofthe corresponding compounds for purposes of the invention.

The following processes may be employed to produce compounds of generalstructural formula I.

A. A compound of general formula II may be reacted with compound III inthe presence of base to produce compounds of general structural formulaI. ##STR8## Representative examples of appropriate bases are pyridineand triethylamine. L designates a suitable leaving group. For example,if Z is 0 or S, a compound of compound III may be an acyl halide (e.g.,L=halo) or acyl anhydride, (e.g., L is ##STR9## Alternatively, if theleaving group is hydroxy, a coupling reagent may be employed to formCompound I. Examples of coupling agents includeN,N'-dicyclohexylcarbodiimide (DCC) and N,N'-carbonyldiimidazole (CDI).The leaving group may also be alkoxy, in which case the compounds offormula I may be produced by refluxing a compound of formula II with anexcess of a compound of formula III.

If compound III is a compound R--CH₂ --L, L can be any easily displacedgroup, such as halo, p-toluene sulfonyloxy, methyl sulfonyloxy,trifluoromethylsulfonyloxy and the like.

Compounds of general formula II may be prepared by cleaving the groupCOOR^(a) from the corresponding carbamates IV, for example, via acidhydrolysis (e.g., HCl) or base hydrolysis (e.g., KOH): ##STR10## whereinR^(a) is a group which does not prevent the cleavage reaction, e.g.,R^(a) is an optionally substituted alkyl such as ethyl.

Alternatively, depending upon the nature of R^(a), as determined by oneskilled in the art, Compound IV may be treated with an organometallicreagent (e.g., CH₃ Li), a reductive reagent (e.g., Zn in acid), etc., toform compounds of formula II.

Compound IV may be prepared from the N-alkyl compound shown as formula Vbelow, in the manner disclosed in U.S. Pat. Nos. 4,282,233 and4,335,036. ##STR11##

It also will be apparent to one skilled in the art that there are othermethods for converting Compound V to Compound II. For example, treatmentof Compound V with BrCN via yon Braun reaction conditions would providenitrile IVa. Subsequent hydrolysis of the nitrile under either aqueousbasic or acidic conditions would produce Compound II. This method ispreferable when there is substitution on the piperidine or piperazinering. ##STR12##

B. The compounds of formula I where Z is O or S may be made by analternative process using direct conversion of the N-alkyl compound Vwith an appropriate compound of formula III such as an acyl halide oracyl anhydride. Preferably the reaction is run in the presence of anappropriate nucleophile (e.g. LiI, etc.) and solvent (e.g., toluene,dioxane or xylenes). An appropriate base, may be added, and heating maybe required. Typically, a temperature ranging from 50°-150° C.(preferably 100°-120° C.) is utilized. ##STR13## Compound V is preparedas described in part A above.

PREPARATION OF DOUBLE BOND COMPOUNDS

Compounds of the formula Ia, where X is a carbon atom having anexocyclic double bond to carbon 11, may be prepared from compound Va asdescribed above. Compounds of formula Va may be produced by the methodsdisclosed generally in U.S. Pat. No. 3,326,924 or alternatively may beprepared by a ring closure reaction, wherein the desired cycloheptenering is formed by treating compound VI with a super acid. Suitable superacids for this purpose include, for example, HF/BF₃, CF₃ SO₃ H (triflicacid), CH₃ SO₃ H/BF₃, etc. The reaction can be performed in the absenceof, or with, an inert co-solvent such as CH₂ Cl₂. The temperature andtime of the reaction vary with the acid employed. For example, withHF/BF₃ as the super acid system the temperature may be controlled so asto minimize side reactions, such as HF addition to the exocyclic doublebond. For this purpose, the temperature is generally in the range offrom about +5° C. to -50° C. With CF₃ SO₃ H as the super acid system,the reaction may be run at elevated temperatures, e.g., from about 25°C. to about 150° C. and at lower temperatures but the reaction thentakes longer to complete.

Generally the super acid is employed in excess, preferably in amounts offrom about 1.5 to about 30 equivalents. ##STR14## A ketone compound offormula VI may be formed by hydrolysis of VII e.g., such as by reactinga Grignard intermediate of formula VII with an aqueous acid (e.g.,aqueous HCl). I^(a) in formula VII represents chloro, bromo or iodo.##STR15##

The Grignard intermediate VII is formed by the reaction of the cyanocompound VIII with an appropriate Grignard reagent IX prepared from1-alkyl-4-halopiperidine. The reaction is generally performed in aninert solvent, such as ether, toluene, or tetrahydrofuran, under generalGrignard conditions e.g., temperature of from about 0° C. to about 75°C. Alternatively, other organometallic derivatives of the 1-alkyl-4-halopiperidine can be employed. ##STR16##

The cyano compound of formula-VIII is produced by converting thetertiary butyl amide of formula X with a suitable dehydrating agent,such as POCl₃, SOCl₂, P₂ O₅, toluene sulfonyl chloride in pyridine,oxalyl chloride in pyridine, etc. This reaction can be performed in theabsence of or with a co-solvent, such as xylene.

The dehydrating agent such as POCl₃ is employed in equivalent amounts orgreater and preferably in amounts of from about 2 to about 15equivalents. Any suitable temperature and time can be employed forperforming the reaction, but generally heat is added to accelerate thereaction. Preferably the reaction is per formed at or near reflux.##STR17##

The tert-butylamide of formula X may be produced by reaction of acompound of formula XIa and XIb, in the presence of base, where G ischloro, bromo or iodo. ##STR18##

The compound of formula XIa may be formed by hydrolysis of thecorresponding nitrile wherein the appropriate cyanomethyl pyridine, suchas 2-cyano-3-pyridine, is reacted with a tertiary butyl compound inacid, such as concentrated sulfuric acid or concentrated sulfuric acidin glacial acetic acid. Suitable tertiary butyl compounds include, butare not limited to, t-butyl alcohol, t-butyl chloride, t-butyl bromide,t-butyl iodide, isobutylene or any other compound which under hydrolyticconditions forms t-butyl carboxamides with cyano compounds. Thetemperature of the reaction will vary depending upon the reactants, butgenerally the reaction is conducted in the range of from about 50° C. toabout 100° C. with t-butyl alcohol. The reaction may be performed withinert solvents, but is usually run neat.

An alternative process for the formation of compounds having generalstructural formula Ia involves direct cyclization of the Compound XII asshown below. ##STR19##

Cyclization to form the cycloheptene ring is accomplished with a strongacid (e.g., triflic, polyphosphoric, HF/BF₃), and may be performed in aninert solvent, such as ether, toluene or THF. The temperature and timemay vary with the acid employed, as described in process A above.

Compounds of formula XII where Z═O or S may be prepared by treating acompound of formula VI with an appropriate acyl halide or acyl anhydrideof formula III. Most preferably this reaction is run in the presence ofa good nucleophile, such as LiI, in the appropriate solvent, such astoluene, dioxane or xylene, and at a temperature ranging from 50°-150°C., preferably 100°-120° C. ##STR20##

A second method of preparing compounds of formula XII involves reactingan unsubstituted piperidylidene compound of formula XIV with theappropriate acyl halide or acyl anhydride of formula III in the presenceof base, such as pyridine or triethylamine. Alternatively, if L═OH incompound III, then coupling of compound XIV with compound III mayrequire use of a conventional coupling reagent, such as DCC or CDI. Ifcompound III is of the formula RCH₂ L, compounds of formula I where Z=H₂ will be produced. In such case, the leaving group can be any easilydisplaced group, such as halo, p-toluene sulfonyloxy, methylsulfonyloxy, trifluoromethyl sulfonyloxy, etc. ##STR21##

Compounds of formula XIV are produced from the corresponding carbamatesof formula XV, via acid hydrolysis, using for example, aqueoushydrochloric acid, or base hydrolysis using for example, potassiumhydroxide. Alternatively, some compounds can be prepared by treating thecarbamate, formula XV, with an organometallic reagent, such as methyllithium or a reductive reagent, such as zinc in acid, etc., dependingupon the nature of the R^(a) group. For example, if R^(a) is a simplealkyl group, CO₂ R^(a) may be cleaved by alkaline hydrolysis at 100° C.##STR22##

The carbamate compounds of formula XV may be prepared from theappropriate alkyl compound of formula VI by treatment with achloroformate, preferably in an inert solvent, such as toluene, withwarming to approximately 80° C. Other alternative methods are availablefor the conversion of XIII to XII as previously described (e.g. YonBraun reaction conditions). ##STR23## Compounds of formula VI may beprepared as described in process A above.

PREPARATION OF PIPERAZINE ANALOGS

Compounds of the piperazine type Ib, where X is N in formula I, are bestprepared via alkylation of the appropriately substituted piperazineCompound XVI with Compound XVII containing the appropriately substitutedhalide (such as Cl, Br, I) or other similar leaving group (tosyloxy ormesyloxy). The reaction usually is conducted in an inert solvent such asTHF or toluene, optionally with a base such as triethylamine orpotassium carbonate, typically at a temperature range of ambient toreflux to produce Compound XVIII. ##STR24## In this reaction R^(c) is H,CO₂ R^(a), C(Z)R or alkyl. The preparation of compound XVII where L isCl is analogous to the procedure described in U.S. Pat. No. 3,409,621.When R^(c) is C(Z)R, compounds of the invention are prepared. When R^(c)is H, alkyl or CO₂ R^(a), the compounds are converted to compounds ofthe invention by processes previously described herein.

An alternative route for generating Compound XVIII is by reductiveamination of the aza ketone XIX with the appropriately substitutedpiperazine XVI. ##STR25##

The reaction typically is carried out in a polar solvent, such asmethanol or ethanol optionally in the presence of a dehydrating agentsuch as 3 Å molecular sieves. The intermediate Schiff base can bereduced to Compound XVIII by employing a variety of reducing agents suchas NaCNBH₃ or catalytic hydrogenation, for example, hydrogen over Pd/C.

When R^(c) is C(Z)R, these are the compounds of the present invention.When R^(c) is H, CO₂ R^(a) or alkyl, these are converted to compounds ofthe invention as previously described.

PREPARATION OF SINGLE BOND COMPOUNDS

Compounds of the formula Ic, where X is a carbon atom having a singlebond to carbon atom 11, may be prepared by the following methods.

A. Compounds of formula VI may be converted to the corresponding alcoholCompound XX by employing an appropriate reducing agent. The reductioncan be accomplished with a variety of reducing agents (e.g. NaBH₄ orLiAlH₄) in an inert solvent such as THF or ether. ##STR26## Compound XXmay be cyclized to Compound XXI via a variety of methods. For example,the cyclization may be conducted under conditions similar to thosedescribed for the cyclization of compound VI to compound V using, forexample, PPA or triflic acid. ##STR27## The alkyl substituted compoundthen may be converted to a compound of the present invention bypreviously described methods.

B. Alternatively, compounds of the invention can be prepared fromcompound XII by methods similar to those described with respect to thereduction of compound XII to compound XXII, and the cyclization ofcompound XXII to compound Ic. ##STR28##

In formula XXIII the double bond can be catalytically hydrogenated toCompound XXIV by a variety of catalysts, such as Pt, Rh, Ru or Pd onvarious supports as described in U.S. Pat. Nos. 3,419,565; 3,326,924;and 3,357,986. ##STR29##

Alternatively, the double bond can be isomerized to the bridgehead usinga superacid, such as triflic acid at high temperature (e.g. 150°-200°C.) to produce Compound XXV. Subsequent catalytic hydrogenationpreferably using Rh or Ru will then provide Compound XXIV. ##STR30##When R^(c) is C(Z)R the compounds of formula XXIV are compounds of thepresent invention. When R^(c) is H, alkyl or CO₂ R^(a) the compounds areconverted to compounds of the present invention as previously described.

C. A third method for the preparation of the subject compounds is by theuse of the appropriately substituted Grignard reagent XXVI (or othercorresponding metalated reagent M, e.g., organolithium, etc.). CompoundXXVI can be reacted with compound XVII where L is a leaving group (e.g.chloride) to provide the desired Compound XXI. ##STR31## These reactionsgenerally are conducted in an inert solvent such as ether, toluene, orTHF at a temperature range of about -78° to about +50° C.

Alternatively, the metalating substituent and the leaving substituentcould be interchanged and reacted under the same conditions to producethe same compound XXI. ##STR32## Compound XXI can be converted tocompounds of the invention as previously described. Further details onthese processes are described in U.S. Pat. Nos. 3,419,565; 3,326,924;3,357,986 and in Org. Chem. 50 p. 339 (1985).

D. Alternatively, compounds of formulae XXVI and XXVII, the preparationof which is disclosed in U.S. Pat. Nos. 3,419,565; 3,326,924; and3,357,986, can be used to provide Compound XXI. This can be accomplishedby reductive removal of the alcohol under a variety of conditions e.g.the methods disclosed in J.A.C.S. 104 p. 4976 (1982) and in J. Org.Chem. 50 p. 339 (1985). ##STR33## Compound XXI may be converted tocompounds of the present invention as previously described.

SUBSTITUTION ON THE BRIDGEHEAD

The following process may be employed to produce compounds of structuralformula I substituted at one or more of the bridgehead carbon atoms. Forthe compounds XXX through XXXIII which are substituted at one bridgeheadcarbon atom, the substitution group shown may have a bond drawn into thecycloheptane ring through the bridgehead, rather than to a specificbridgehead carbon atom. This is used to indicate that attachment of thesubstitution group to a particular bridgehead carbon atom is a functionof the starting compound. For example, if the methoxy group of compoundXXXI below is attached to bridgehead carbon 5, the carbonyl group on thebridgehead of compound XXXIII will be positioned at carbon 5 also.However, both isomers substituted at positions 5 and/or 6 arecontemplated as being within the scope of the invention.

By substituting an isomer of the precursor compound, a compound can besynthesized having the substitution on the bridgehead carbon atomsdifferent from that disclosed in the drawing. ##STR34##

The bridgehead of Compound XXVIII, which is disclosed in U.S. Pat. No.3,326,924, is first brominated with an appropriate brominating agent,such as N-bromosuccinimide (NBS) in the presence of an initiator, suchas azobisisobutyryl nitrile (ABIN), benzoyl peroxide or the like in aninert solvent, such as CCl₄, benzene or a similar solvent. Heat or lightmay be required to initiate the reaction. The bromine on the bridgeheadmay then be eliminated with base to form the olefinic Compound XXIX.Examples of suitable bases for elimination include diazabicycloundecane(DBU), diazabicyclononane (DBN) and diazabicyclooctane (DABCO).Elimination is typically performed in an inert solvent at refluxtemperature. Examples of suitable inert solvents include CH₂ Cl₂, CCl₄,toluene, tetrahydrofuran (THF), dioxane, and CHCl₃, with CHCl₃ beingpreferred.

Alternatively, Compound XXVIII may be refluxed in the presence of anoxidizing agent to yield compound XXIX. Representative examples ofoxidizing agents suitable for oxidizing Compound XXVIII include2,3-dichloro-5,6-dicyano-1,4-quinone (DDQ) and SeO₂. ##STR35##

Compound XXIX may be converted to Compound XXX by adding excess powderedAgNO₃ in methanol, followed by the addition of excess Br₂, whichbromoetherificates the unsubstituted bridgehead carbon atom. Thebridgehead bromine is then eliminated with excess base, such as DBU toprovide a compound of formula XXX. The reaction may be run in an inertsolvent such as CHCl₃ at reflux temperature. The resultant isomericmixture may be separated by column chromatography or any otherappropriate method. ##STR36##

A compound of formula XXXI is prepared by treating the 5-substituted or6-substituted isomer represented by compound XXX with a Grignard reagentXXVI or similar metalated reagent in an inert solvent, such as ether,benzene, or tetrahydrofuran (THF). Compound XXVI is prepared in a knownmanner from magnesium and the 4-chloro N-substituted piperidine. Thereaction may be refluxed if necessary, after which it may be quenchedwith NH₄ Cl to form compound XXXI. ##STR37##

A compound of formula XXXI may be hydrolyzed with any strong, aqueousacid, for example, 80-95% H₂ SO₄ or HCl, having a pH less than 1, at atemperature not higher than room temperature for not generally longerthan one hour to produce an intermediate compound of formula XXXII.

After complete hydrolysis, compound XXXII may be dehydrated with CF₃ SO₃H (triflic acid) or a similar acid to yield compound XXXIII. Examples ofother acids for dehydrating compound XXXII at carbon atom 11 include,for example, HF/BF₃, CH₃ SO₃ H/BF₃, etc. The reaction can be performedin the absence of or with an inert co-solvent such as CH₂ Cl₂. Thetemperature and time of the reaction vary with the acid employed. Whentriflic acid is used as the super acid system, the temperature may becontrolled to minimize side reactions. For example, Compound XXXIIhaving a carbonyl at carbon atom 5 is best dehydrated when thetemperature is maintained in the range of from about 40° C. to about 80°C., preferably about 75° C. Alternatively, dehydration of a compoundhaving a carbonyl at carbon atom 6 is best accomplished at elevatedtemperatures, such as from about 100° C. to 130° C.

Compound XXXIII can then be converted to compounds of the invention aspreviously described.

Ketone XXX can be reduced to the corresponding alcohol XXXIV using avariety of reducing agents (e.g. NaBH₄ in MeOH, LiAlH₄ in ether). Thealcohol can then be converted to an appropriate leaving group (L) suchas halide (e.g. Cl, Br, I) or other derivative (e.g. tosyloxy) therebyproviding compound XXXV. For example, the chloride of XXXV (L═Cl) can beobtained from the alcohol using SOCl₂ in an inert solvent such astoluene. ##STR38##

Alkylation of the appropriately substituted piperazine compound XVI withXXXV then provides XXXVI. The reaction is usually conducted in an inertsolvent such as THF or toluene, optionally with base, such astriethylamine or potassium carbonate, typically at ambient to refluxtemperature. ##STR39## Compound XXXVI can then be hydrolyzed with anystrong aqueous acid, for example 80-95% H₂ SO₄ or HCl to provide thedesired keto compound XXXVII. ##STR40##

The bridgehead carbonyl of compound XXXVIII or XXXIII may be reduced toan hydroxy group by treating compound XXXVIII with an appropriatereducing agent, such as NaBH₄ in CH₃ OH or LiAlH₄ in ether to produce acompound of formula XXXIX. ##STR41##

Compounds XXXIX, XXXVII or XXXII may be used to generate othersubstitutions in the bridgehead using available methods.

When R^(c) is C(Z)R, compounds of the invention are prepared. When R^(c)is H, CO₂ R^(a) or alkyl, such compounds can be converted to compoundsof the invention as previously described.

Where Z represents sulfur, a compound of formula I where Z is oxygen isreacted with P₂ S₅, Lawesson's reagent, or another reagent capable ofintroducing sulfur in place of oxygen.

The reaction may take place at elevated temperature in pyridine, tolueneor other suitable solvents. Lawesson's reagent has the formula ##STR42##

In this and other reactions, numerous conversions of a compound offormula I (Z═O) to another compound of formula I (Z═S) are possible.

In the above processes, it is sometimes desirable and/or necessary toprotect certain R¹, R², R³ and R⁴ etc., groups during the reactions.Conventional protecting groups are operable. For example, the groupslisted in column 1 of the following table may be protected as indicatedin column 2 of the table:

    ______________________________________                                        1. Group to be Protected                                                                       2. Protected Group                                           ______________________________________                                        COOH             COOalkyl, COObenzyl,                                                          COOphenyl                                                     ##STR43##       NCO.sub.2 alkyl, NCO.sub.2 benzyl, NCO.sub.2 CH.sub.2                         OCl.sub.3                                                     ##STR44##                                                                                      ##STR45##                                                   OH                                                                                              ##STR46##                                                   NH.sub.2                                                                                        ##STR47##                                                   ______________________________________                                    

Other protecting groups well known in the art also may be used. Afterthe reaction or reactions, the protecting groups may be removed bystandard procedures.

The compounds of the invention possess platelet-activating factor("PAF") antagonistic properties. The compounds of the invention are,therefore, useful when PAF is a factor in the disease or disorder. Thisincludes allergic diseases such as asthma, adult respiratory distresssyndrome, urticaria and inflammatory diseases such as rheumatoidarthritis and osteoarthritis. For example, PAF is an important mediatorof such processes as platelet aggregation, smooth muscle contraction(especially in lung tissue), vascular permeability and neutrophilactivation. Recent evidence implicates PAF as an underlying factorinvolved in airway hyperreactivity.

The PAF antagonistic properties of these compounds may be demonstratedby use of standard pharmacological testing procedures as describedbelow. These test procedures are standard tests used to determine PAFantagonistic activity and to evaluate the usefulness of said compoundsfor counteracting the biological effects of PAF. The in vitro assay is asimple screening test, while the in vivo test mimics clinical use of PAFantagonists to provide data which simulates clinical use of thecompounds described herein.

A. PAF ANTAGONISM ASSAY

In vitro Assay:

Preparation of platelet-rich plasma (PRP): Human blood (50 ml) wascollected from healthy male donors in an anticoagulant solution (5 ml)containing sodium citrate (3.8%) and dextrose (2%). Blood wascentrifuged at 110×g for 15 min. and the supernatant PRP carefullytransferred into a polypropylene tube. Platelet-poor-plasma (PPP) wasprepared by centrifuging PRP at 12,000×g for 2 min. in a BeckmanMicrofuge B. PRP was used within 3 hours of drawing the blood.

Platelet Aggregation Assay: When an aggregating agent such as PAF isadded to PRP, platelets aggregate. An aggregometer quantifies thisaggregation by measuring light (infra-red) transmission through PRP andcomparing to PPP. The aggregation assays were performed using adual-channel aggregometer (Model 440, Chrono-Log Corp., Hayertown, Pa.).PRP (0.45 ml) in aggregometer curettes was continually stirred (37° C.).Solutions of test compounds or vehicle were added to the PRP, and afterincubation for 2 min., 10-15 μl aliquots of PAF solution were added soas to achieve a final concentration of 1-5×10⁻⁸ M. Incubations werecontinued until the increase in light transmission reached a maximum(usually about 2 min). Values for inhibition were calculated bycomparing maximal aggregation obtained in the absence and the presenceof the compound. For each experiment, a standard PAF antagonist, such asalprazolam, was used as a positive internal control. The inhibitoryconcentration (IC₅₀) is the concentration of compound in micromoles atwhich 50% of the aggregation is inhibited, as measured by the lighttransmission through each sample of PRP as compared to PPP. The testresults are shown below in Tables Ia, Ib and Ic.

PAF is also a known bronchoconstrictive agent in mammals. Hence, PAFantagonism can be evaluated by measuring inhibition by the compounds ofthe invention in PAF-induced bronchoconstriction in guinea pigs.

B. PAF-INDUCED BRONCHOSPASM IN GUINEA PIGS

In Vivo Assay

Non-sensitized guinea Digs were fasted overnight, and the followingmorning were anesthetized with 0.9 ml/kg i.p. of dialurethane (0.1 g/mlof diallybarbituric acid, 0.4 g/ml of ethylurea and 0.4 g/ml ofurethane). The trachea was cannulated and the animals were ventilated bya Harvard rodent respirator at 55 strokes/min. with a stroke volume of 4ml. A side arm to the tracheal cannula was connected to a Harvardpressure transducer to obtain a continuous measure of intratrachealpressure, which was recorded on a Harvard Polygraph. The jugular veinwas cannulated for the administration of compounds. The animals werechallenged i.v. with PAF (0.4 ug/kg in isotonic saline containing 0.25%BSA) and the peak increase in inflation pressure that occurred within 5min. after challenge was recorded. Test compounds were administeredeither orally (2 hrs. prior to PAF as a suspension in 0.4%methylcellulose vehicle) or intravenously (10 min. prior to PAF as asolution in dimethylsulfoxide).

The compound8-chloro-11-(1-acetyl-4-piperidylidene)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridineat a dose of 1 mg/kg given intravenously inhibited PAF-inducedbronchospasm by 75% as measured by this procedure. Similarly, thecompound8-fluoro-11-(1-acetyl-4-piperidylidene)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridinewhen administered at 3 mg/kg (iv) inhibited PAF-induced bronchospasm by99%. The compound9-fluoro-11-(1-acetyl-4-piperidylidene)-6,11-dihydro-5H-benzo[5,6]cyclopheta[1,2-b]pyridinewhen administered at 3 mg/kg (iv) inhibited PAF-induced bronchospasm by97%.

The compounds of the invention also possess antihistaminic propertieswhich may be assessed by test procedure C below. Test procedure C,"Prevention of histaminic-induced lethality" demonstrates basicantihistaminic activity of representative compounds of structuralformula I. Protection against histamine lethality is indicative ofstrong antihistaminic properties.

Test procedures D, E and F demonstrate the extent of CNS activityinduced by the compounds of the invention. The presence of strong CNSactivity indicates a high probability of sedation caused by thecompounds, a typically undesirable side effect of antihistamines.Consequently, a low level of CNS activity is preferred in mostcircumstances.

C. ANTIHISTAMINE ACTIVITY ASSAY

Prevention of Histamine-Induced Lethality in Guinea Pigs. Some ofcompounds shown below in Table I also were evaluated for antihistamineactivity by their ability to protect female albino guinea pigs (250-350g) against death induced by the intravenous injection of histaminedihydrochloride at 1.1 mg/kg, which is approximately twice the LD₉₉.Doses of the antagonists were administered orally to separate groups offasted animals 1 hour prior to the challenge with histamine andprotection from death recorded for 30 minutes after histamine. ED₅₀values were determined for each drug by probit analysis.

CNS ACTIVITY ASSAYS

D. Antagonism of Physostigmine Lethality. The physostigmine-inducedlethality test is indicative of CNS activity and the test described is amodification of the technique reported by COLLIER et al., Br. J.Pharmac., 32, 295-310 (1968). physostigmine salicylate (1.0 mg/kg s.c.)produces 100% lethality when administered to mice grouped 10 per plasticcage (11×26×13 cm). Test agents were administered orally 30 minutesprior to physostigmine. The number of survivors were counted 20 minutesafter physostigmine administration.

E. Antagonism of Acetic Acid Writhing. The acetic acid writhing test isa second test useful for determining CNS activity, and is essentiallythat described by HENDERSHOT and FORSAITH, J. Pharmac. Exp. Ther., 125,237-240 (1959), except that acetic acid rather than phenylquinone wasused to elicit writhing. Mice were injected with 0.6% aqueous aceticacid at 10 mg/kg i.p. 15 minutes after oral administration of the testdrug. The number of writhes for each animal was counted during a 10minute period starting 3 minutes after acetic acid treatment. A writhewas defined as a sequence of arching of the back, pelvic rotation andhind limb extension.

F. Antagonism of Electro-Convulsive Shock (ECS). The ECS test is a thirdtest useful for determining CNS activity. For the ECS test, amodification of the method of TOMAN et al., J. Neurophysiol., 9, 231-239(1946), was used. One hour after oral administration of the test drug orvehicle, mice were administered a 13 mA, 60 cycle a.c. electroconvulsantshock (ECS) for 0.2 seconds via corneal electrodes. This shock intensityproduces tonic convulsions, defined as extension of the hind limbs, inat least 95% of vehicle-treated mice.

Of the above test procedures for measuring CNS activity, thephysostigmine-induced lethality test is believed to be a major index ofnon-sedating characteristics, since it reflects mainly centralanticholinergic potency which is believed to contribute to sedativeactivity.

Representative results of these test procedures with compounds of theinvention are presented below in Tables IA, IB and IC.

                                      TABLE IA                                    __________________________________________________________________________                      Antihistaminic Activity                                                                   CNS Activity                                                      Guinea pig  Physostigmine                                                                         Acetic                                                                              ECS                                                 oral dose   lethality                                                                             writhing                                                                            test PAF Antagonism (in                                                            vitro)                                         (mg/kg)     ED.sub.50                                                                             ED.sub.50                                                                           ED.sub.50                                                                          Dose   % PAF                 Compound          Dose  % Survival                                                                          (mg/kg) (mg/kg)                                                                             (mg/kg)                                                                            (micromoles)                                                                         Antagonism            __________________________________________________________________________     ##STR48##                                                                    Z = S, R = Ph     5 PO  60    >320    >320  >320 *      *                     R.sup.3 = Cl, R.sup.4 = H                                                                       1 PO   0                                                    Z = O R = CH.sub.3                                                                              5 PO  100   >320    >160  >320 0.7    50                    R.sup.3 = Cl R.sup.4 =  H                                                                       1 PO  60                                                    Z = O R = Ph      5 PO  100   *       *     *    10     9                     R.sup.3 = Cl R.sup.4 = H                                                                        1 PO   0                                                    R = CH.sub.2 OCH.sub.3                                                                          5 PO  80    >320    >320  >320 6      50                    R.sup.3 = Cl R.sup.4 = H                                                                        1 PO  80                                                    Z = O                                                                         R = CH.sub.2 CH.sub.2 CH.sub.3                                                                  5 PO  100   >320    >320  >320 *      *                     R.sup.3 = Cl R.sup.4 = H                                                                        1 PO  40                                                    Z = O                                                                         R = SCH.sub.2 CH.sub.3                                                                          5 PO  80    >320    >320  >320 10     0                     R.sup.3 = Cl R.sup.4 = H                                                                        1 PO  100                                                   Z = O                                                                         R = CH.sub.2 CH.sub.2                                                                           5 PO  80    >320    >320  >320 3      60                    R.sup.3 = Cl R.sup.4  = H                                                                       1 PO  40                                                    Z = O                                                                         R = CH.sub.2 OCH.sub.3                                                                          5 PO  100   <320    <320  <320 10     9                     R.sup.3 = F R.sup.4 = H                                                                         1 PO  100                                                   Z = O                                                                         R = CH.sub.3 Z = O                                                                              5 PO  20    *       *     *    0.7    50                    R.sup.3 = F R.sup.4 = H                                                       R = CH.sub.3 Z = O                                                                              5 PO  .sup. *0.sup.1                                                                              *     *    0.9    50                    R.sup.3 = H R.sup.4 = F                                                       R.sup.3 = Br, R.sup.4 = H,                       1.2    50                    R = CH.sub.3 Z = O                                                             ##STR49##                                       5      35                    R.sup.3 =  Cl, R.sup.4 = H                       25     63                    R = CHCH.sub.2 Z = O                                                          R.sup.3 = Cl, R.sup.4 = H                        50     29                    R = NHCH.sub.3                                                                Z = O                                                                          ##STR50##                                                                    R.sup.3 = Cl, R.sup.4 = H                        5      50                    R = CH.sub.3 Z = O                                                            A = OH                                                                        R.sup.3 = Cl, R.sup.4 = H                        1.0    50                    R = CH.sub.3 Z = O                                                            A = CH.sub.3                                                                  R.sup.3 = Cl, R.sup.4 = H                        1.2    50                    R =  CH.sub.3 Z = O                                                           A = Keto                                                                      R.sup.3 = H, R.sup.4 = H                                                                        ED.sub.50 =   6.1     8.9  >80 >100   50                    A = H             0.009                                                       CZR = CH.sub.3 **                                                             R = OC.sub.2 H.sub.5 **                                                                         ED.sub.50 = >320    >320  >320 175    50                    R.sup.3 = Cl, R.sub.4 = H                                                                       0.19                                                        Z = O                                                                         __________________________________________________________________________     *Not Tested                                                                   **Standard Known Antihistamine                                                .sup.1 Expected to have some activity at a higher dose                   

                  TABLE IB                                                        ______________________________________                                        PAF Antagonism (in vitro)                                                                        Dose       % PAF                                           Compound           (micromoles)                                                                             Antagonism                                      ______________________________________                                         ##STR51##                                                                    R.sup.3 = H, R.sup.4 = H                                                                         5          50                                              R = CH.sub.3 Z = O                                                            X = CH                                                                        R.sup.3 = Cl, X = N                                                                              .5         43                                              R = CH.sub.3 Z = O                                                            R.sup.4 = H                                                                   R.sup.3 = Cl, X = N                                                                              5          50                                              R = H Z = O                                                                   R.sup.4 = H                                                                   R.sup.3 = Cl, X = N                                                                              5          50                                              R = CH.sub.2 OCH.sub.3                                                        Z =  O                                                                        R.sup.4 = H                                                                    ##STR52##         5          63                                              ______________________________________                                         *Not tested                                                                   **Standard known antihistamine.                                          

                  TABLE IC                                                        ______________________________________                                                            PAF Antagonism                                                                (in vitro)                                                                      Dose                                                                          (micro-  % PAF                                          Compound              moles)   Antagonism                                     ______________________________________                                         ##STR53##            .5       50                                              ##STR54##            .12      44                                              ##STR55##            1.5      50                                              ##STR56##            5        58                                              ##STR57##            2.5      53                                             ______________________________________                                    

As seen from the data of Tables IA, IB and IC and from the PAF inducedbronchospasm inhibition test results, the compounds of structuralformula I exhibit PAF antagonist and antihistaminic properties tovarying degrees, i.e., certain compounds have strong PAF antagonisticactivity, but have weaker antihistaminic activity. Other compounds arestrong antihistamines but weaker PAF antagonists. Several of thecompounds are both strong PAF antagonists and potent antihistamines.Consequently, it is within the scope of this invention to use each ofthese compounds when clinically appropriate. For example, if a strongPAF antagonist is required, but weaker antihistaminic activity isnecessary, such a compound could be chosen by the clinician.Alternatively, if both potent PAF antagonism and antihistaminic activityare required, a different compound of the invention would be utilized bythe clinician.

For preparing pharmaceutical compositions from the compounds describedby this invention, inert, pharmaceutically acceptable carriers can beeither solid or liquid. Solid form preparations include powders,tablets, dispersible granules, capsules, cachets and suppositories. Thepowders and tablets may be comprised of from about 5 to about 70 percentactive ingredient. Suitable solid carriers are known in the art, e.g.magnesium carbonate, magnesium stearate, talc, sugar, lactose. Tablets,powders, cachets and capsules can be used as solid dosage forms suitablefor oral administration.

For preparing suppositories, a low melting wax such as a mixture offatty acid glycerides or cocoa butter is first melted, and the activeingredient is dispersed homogeneously therein as by stirring. The moltenhomogeneous mixture is then poured into convenient sized molds, allowedto cool and thereby solidify.

Liquid form preparations include solutions, suspensions and emulsions.As an example may be mentioned water or water-propylene glycol solutionsfor parenteral injection.

Liquid form preparations may also include solutions for intranasaladministration.

Aerosol preparations suitable for inhalation may include solutions andsolids in powder form, which may be in combination with apharmaceutically acceptable carrier, such as an inert compressed gas.

Also included are solid form preparations which are intended to beconverted, shortly before use, to liquid form preparations for eitheroral or parenteral administration. Such liquid forms include solutions,suspensions and emulsions.

The compounds of the invention may also be deliverable transdermally.The transdermal compositions can take the form of creams, lotions,aerosols and/or emulsions and can be included in a transdermal patch ofthe matrix or reservoir type as are conventional in the art for thispurpose.

Preferably the compound is administered orally.

Preferably, the pharmaceutical preparation is in unit dosage form. Insuch form, the preparation is subdivided into unit doses containingappropriate quantities of the active component, e.g., an effectiveamount to achieve the desired purpose.

The quantity of active compound in a unit dose of preparation may bevaried or adjusted from about 0.1 mg to 1000 mg, more preferably fromabout 1 mg. to 100 mg, according to the particular application. Theappropriate dosage can be determined by comparing the activity of thecompound with the activity of a known antihtstaminic compound such as8-chloro-6,11-dihydro-11-(1-ethoxycarbonyl-4-piperidylidene)-5H-benzo[5,6]cyclohepta[1,2-b]pyridine,which compound is disclosed in U.S. Pat. No. 4,282,233.

The actual dosage employed may be varied depending upon the requirementsof the patient and the severity of the condition being treated.Determination of the proper dosage for a particular situation is withinthe skill of the art. Generally, treatment is initiated with smallerdosages which are less than the optimum dose of the compound.Thereafter, the dosage is increased by small increments until theoptimum effect under the circumstances is reached. For convenience, thetotal daily dosage may be divided and administered in portions duringthe day if desired.

The amount and frequency of administration of the compounds of theinvention and the pharmaceutically acceptable salts thereof will berequlated according to the judgement of the attending clinicianconsidering such factors as age, condition and size of the patient aswell as severity of the symptom being treated. A typical recommendeddosage regimen is oral administration of from 10 mg to 1500 mg/daypreferably 10 to 750 mg/day, in two to four divided doses to achieverelief of the symptoms. The compounds are non-toxic when administeredwithin this dosage range.

The following examples are intended to illustrate, but not to limit, thepresent invention.

PREPARATIVE EXAMPLE I

A. N-(1,3-DIMETHYLETHYL)-3-METHYL-2-PYRIDINE CARBOXAMIDE ##STR58##

Suspend 2-cyano-3-methyl pyridine (400 g) in t-butanol (800 mL) and heatto 70° C. Add concentrated sulphuric acid (400 mL) dropwise over 45minutes. Maintain the temperature at 75° C., until the reaction iscomplete, and for an additional 30 minutes. Dilute the mixture withwater (400 mL), charge with toluene (600 mL) and bring to pH 10 withconcentrated aqueous ammonia. Maintain the temperature at 50°-55° C.during the work up. Separate the toluene phase, and reextract theaqueous layer. Combine toluene phases and wash with water. Remove thetoluene to yield the title compoundN-(1,1-dimethylethyl-(3-methyl-2-pyridine carboxamide, as an oil, fromwhich solid product is crystallized. (Yield 97%, as determined by aninternal standard assay with gas chromatography).

B. 3-[2-(3-CHLOROPHENYL)ETHYL]-N-(1,1-DIMETHYLETHYL)-2-PYRIDINECARBOXAMIDE ##STR59##

Dissolve the title compound of Preparative Example 1A,N-(1,1-dimethylethyl)-3-methyl-2-pyridine carboxamide (31.5 g.) intetrahydrofuran (600 mL) and cool the resulting solution to -40° C. Addn-butyllithium (2 eg.) in hexane while maintaining the temperature at-40° C. The solution turns deep purple-red. Add sodium bromide (1.6 g)and stir the mixture. Add solution of m-chlorobenzylchloride (26.5 g.,0.174 mole) in tetrahydrofuran (125 mL) while maintaining thetemperature at -40° C. Stir the reaction mixture until the reaction iscomplete as determined by thin layer chromatography. Add water to thereaction until the color is dissipated. Extract the reaction mixturewith ethyl acetate, wash with water, and concentrate to a residue whichis the title compound. (Yield 92% as shown by chromatography).

C. 3-[2-(3-CHLOROPHENYL)ETHYL]-2-PYRIDINE-CARBONITRILE ##STR60##

Heat a solution of the title compound of Preparative Example 1B,3-[2-(3-chlorophenyl)ethyl]-N-(1,1-dimethylethyl)-2-pyridine carboxamide(175 g, 0.554 mole) in phosphorous oxychloride (525 mL, 863 g, 5.63mole) and reflux for 3 hours. Determine completion of the reaction bythin layer chromatography. Remove any excess phosphorous oxychloride bydistillation at reduced pressure and quench the reaction in a mixture ofwater and isopropanol. Bring to pH 5-7 by adding 50% aqueous sodiumhydroxide solution while maintaining the temperature below 30° C. Filterthe crystalline slurry of crude product and wash with water. Purify thecrude product by slurrying the wet cake in hot isopropanol, and cool to0°-5° C. Filter the product, wash with hexane and dry at a temperaturebelow 50° C. to yield the title compound. (Yield: 118 g (HPLC purity95.7%), m.p. 72° C.-73° C., 89.4% of theory).

D.1-(METHYL-4-PIPERIDINYL)[3-(2-(3-CHLOROPHENYL)ETHYL)-2-PYRIDINYL]METHANONEHYDROCHLORIDE ##STR61##

Dissolve the title compound of Preparative Example 1C, (118 g, 0.487mole) in dry tetrahydrofuran (1.2L) and add N-methyl-piperidyl magnesiumchloride (395 mL, 2.48 mole/liter, 0.585 mole, 1.2 eq.) over 15 minutes.Maintain the temperature at 40° C.-50° C. by cooling with water asnecessary, for 30 minutes. Determine completion of the reaction bythin-layer chromatography. Quench the reaction by reducing the pH tobelow 2 with 2N HCl and stir the resulting solution at 25° C. for 1hour. Remove the bulk of the tetrahydrofuran by distillation and adjustthe resulting solution to pH 3.5 by addition of aqueous sodiumhydroxide. Cool to 0° to 5° C. and filter off the crystallinehydrochloride salt product. Wash with ice cold water and dry to constantweight at 60° C. to yield the title compound. (Yield: 168.2 g (HPLCpurity 94%), m.p. 183°-185° C. 89% of theory).

E.8-CHLORO-11-(1-METHYL-4-PIPERIDYLIDENE)-6,11-DIHYDRO-5H-BENZO[5,6]CYCLOHEPTA[1,2-b]PYRIDINE##STR62##

Dissolve the title compound of Preparative Example 1D above (59 g, 0.15mole) in hydrofluoric acid (120 mL, 120 g, 6.0 mole) at -35° C. and addboron trifluoridine (44.3 g, 0.66 mole) over 1 hour. Determinecompleteness of the reaction by thin-layer chromatography. Quench thereaction using ice, water and potassium hydroxide bringing the solutionto a final pH of 10. Extract the product with toluene and wash withwater and brine. Concentrate the toluene solution to a residue, anddissolve in hot hexane. Remove the insolubles by filtration andconcentrate the filtrate to yield the title compound as an off-whitepowder. (Yield: 45.7 g (HPLC purity: 95%), 92% of theory).

Alternative Step E:8-CHLORO-11-(1-METHYL-4-PIPERIDYLIDENE)-6,11-DIHYDRO-5H-BENZO[5,6]CYCLOHEPTA[1,2-b]-PYRIDINE

React the title compound of preparative Example 1D above (177 g, 0.49mole) in trifluoromethanesulfonic acid (480 ml, 814.1 g, 5.31 mole) at90°-95° C. for 18 hours under nitrogen. Determine the completeness ofthe reaction by thin-layer chromatography. Cool the reaction and quenchthe reaction with ice-water and adjust the pH to 6 with bariumcarbonate. Extract the product with methylene chloride, and concentrateunder reduced pressure to about 1 liter. Wash with water, and extractthe product into 1N HCl which is treated with 30 g of activatedcharcoal, and filter through celite. Adjust the pH of the filtrate to 10with aqueous sodium hydroxide (50%), extract the product into methylenechloride, and remove under reduced pressure to form a residue. Dissolvethe residue in hot hexane, and filter to remove insolubles. Concentratethe filtrate to yield the title compound as a beige powder. (Yield: 126g (HPLC purity 80%), 65% of theory).

F.8-CHLORO-11-(1-ETHOXYCARBONYL-4-PIPERIDYLIDENE)-6,11-DIHYDRO-5H-BENZO[5,6]CYCLOHEPTA[1,2-b]PYRIDINE##STR63##

Dissolve the title compound of Preparative Example 1E above (45.6 g,0.141 mole) in toluene (320 mL) at 80° C. and to it gradually add ethylchloroformate (40.4 mL, 45.9 g, 0.423 mole). Following completeaddition, maintain the temperature at 80° C. for 1 hour, then adddiisopropylethylamine (2.7 mL, 2.00 g, 0.016 mole) and additional ethylchloroformate (4.1 mL, 4.65 g, 0.0429 mole). Monitor completeness of thereaction by thin layer chromatography. Upon completion, cool thereaction mixture to ambient temperature, and wash the toluene solutionwith water. Concentrate the organic layer to a residue and dissolve inhot acetonitrile (320 mL). Decolorize the solution with 14 g ofactivated charcoal. Remove the activated charcoal by filtration andconcentrate the filtrate to a crystalline slurry. Cool the mixture to0°-5° C., and isolate the product by filtration. Wash with coldacetonitrile and dry the product at below 70° C. to yield the titlecompound. (Yield: 42.4 g (HPLC purity 97.4%), 80% of theory).

G.8-CHLORO-11-(4-PIPERIDYLIDENE)-6,11-DIHYDRO-5H-BENZO[5,6]CYCLOHEPTA[1,2-b]PYRIDINE##STR64##

Hydrolize the title compound of Preparative Example 1E,8-chloro-11-(1-methyl-4-piperidylidene)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine(39 g, 0.101.mole) with KOH (50 g) in ethanol (305 mL) and water (270mL) at reflux under an argon atmosphere for 64 hours. Partially distilloff the ethanol and dilute the residue with brine, and extract withethylacetate (3×). Wash the co,Dined organic phases with water and drywith Na₂ SO₄. Remove the solvent to give a solid which can berecrystallized from toluene to give the title compound as a white solid.(Yield: 24.5 g, 77%, melting point 154°-155° C.).

H. By substituting in step 1B above, an appropriately substituted arylor alkyl halide listed in Table II below for meta-chlorobenzylchloride,and employing basically the same methods as steps C through G, theproducts listed in Table II are prepared by the process of PreparativeExample 1 above. Reaction times are determined by TLC or HPLC. In someinstances purification of the product by chromatography is necessary.

                                      TABLE II                                    __________________________________________________________________________                     Product of step G                                                              ##STR65##                                                   halide           R.sup.3                                                                              R.sup.4                                                                            A     Melting Point                              __________________________________________________________________________       ##STR66##     R.sup.3 = F,                                                                         R.sup.4 = H,                                                                       A = H 133.5-134.5° C..sup.a                  ##STR67##     R.sup.3 = Cl,                                                                        R.sup.4 = Cl,                                                                      A = H 150-152° C..sup.b                      ##STR68##     R.sup.3 = CH.sub.3,                                                                  R.sup.4 = H,                                                                       A = H 142-144° C..sup.c                      ##STR69##     R.sup.3 = Br,                                                                        R.sup.4 = H,                                                                       A = H 146-148° C.                            ##STR70##     R.sup.3 = OCH.sub.3,                                                                 R.sup.4 = H,                                                                       A = H crude solid                                   ##STR71##                                                                                    ##STR72##  A = H glass                                        CH.sub.3 I                                                                    Then repeat step B with                                                      ##STR73##       R.sup.3 = Cl,                                                                        R.sup.4 = H,                                                                       A = CH.sub.3                                                                        glass                                      __________________________________________________________________________     .sup.a Step E required trifluoromethanesulfonic acid.                         .sup.b Recrystallized from toluene.                                           .sup.c Recrystallized from acetone and pentane.                          

PREPARATIVE EXAMPLE 2 PREPARATION OF9-FLUORO-11-(4-PIPERIDYLIDENE)-6,11-DIHYDRO-5H-BENZO[5,6]CYCLOHEPTA[1,2-b]PYRIDINE

A. N-(1,1-DIMETHYLETHYL)-3-[2-(4-FLUOROPHENYL)ETHYL]-2-PYRIDINECARBOXAMIDE ##STR74##

Cool a solution of N-(1,1-dimethylethyl)-3-methyl-2-pyridinecarboxamide(38.4 g, 0.2 mole) in dry THF (250 mL) to -40° C. and add n-butyllithium (185 mL, 0.44 mole). Add sodium bromide (1.9 g, 18 mmol.) andstir for 15 minutes. Add 4-fluorobenzylchloride (31.8 g. 0.22 mole) andstir for 2.5 hours while warming to -5° C. Quench the reaction withwater and extract the product twice with ethyl acetate, then wash withbrine (2×). Dry the organic phase over Na₂ SO₄, filter and remove thesolvent to give the title compound. (60.0 g, Yield 99%, m.p. 59°-61° C.)

B. 3-[2-(4-FLUOROPHENYL)ETHYL]-2-PYRIDINE CARBONITRILE ##STR75##

Heat the title compound of Preparative Example 2A above (60.0 g,0.2mole) in POCl₃ (200 mL) to 110° C. under an argon atmosphere for 3.5hours. Pour the reaction mixture onto ice and basify with NaOH (50%)solution. Extract the mixture with ethyl acetate (3×) and wash withwater. Wash with brine and dry over Na₂ SO₄. Remove the solvent and passthe residue through a coarse SiO₂ (60-200 mesh) column to give the titlecompound as a white solid (40 g, Yield 88%, m.p. 48°-49° C.).

C. 9-FLUORO-5,6-DIHYDRO-(1H)-BENZO[5,6]CYCLOHEPTA[1,2-b]PYRIDIN-11-ONE##STR76##

Cyclize the title compound of Preparative Example 2B above (31.5 g, 139mmol) in polyphosphoric acid (1.24 kg) at 200° C. for 5.5 hours. Pouronto ice and basify with NaOH solution (50%). Extract the product withchloroform (3×) and wash with brine. Dry the organic phase with Na₂ SO₄,filter and remove the solvent to give the title compound (20.4 g, yield64%, m.p. 78°-81° C. after recrystallization from diisopropyl ether).

D.9-FLUORO-11-(1-METHYL-4-PIPERIDINYL)-6,11-DIHYDRO-5H-BENZO[5,6]CYCLOPHEPTA[1,2-b]PYRIDIN-11-OL##STR77##

Dissolve the title compound of Preparative Example 2C above (10.0 g, 44mmol) in THF (100 mL) and add slowly to a cooled (-40° C.) solution ofthe Grignard reagent prepared from N-methyl-4-chloro-piperidiene (57.9ran, 88 mmol) in THF (70 mL). Stir the mixture for about 1 hour whilewarming up to 0° C. Quench the reaction with NH₄ Cl solution and extractwith ethyl acetate (2×). Wash the organic phase with brine and dry overNa₂ SO₄, filter and remove the solvent. Purify the residue with flashchromatography and elute with methanol (5%) in CHCl₃ to give the titlecompound as white granular crystals. (10.1 g, Yield 70%, m.p. 126°-127°C. after recrystallization from diisopropyl ether.)

E.9-FLUORO-11-(1-METHYL-4-PIPERIDYLENE)-6,11-DIHYDRO-5H-BENZO[5,6]CYCLOHEPTA[1,2-b]PYRIDINE##STR78##

Add the title compound of preparative Example 2D above (7.3 g, 22.3mmol) to a mixture of cooled H₂ SO₄ and CF₃ SO₃ H (1:1), 146 mL). Stirthe reaction mixture for 0.5 hours at ice bath temperature and then atroom temperature for 1.5 hours. Pour the reaction mixture onto ice andbasify with NaOH (50%) solution. Extract the product with ethyl acetate(3×) and wash with brine. Dry the organic phase over Na₂ SO₄, filter andremove the solvent to give a crude oil. Charcoal the oil andrecrystallize from ethyl acetate and isopropyl ether to give the titlecompound. (5.6 g, Yield 82%, m.p. 134.5°-135.5° C.).

F.9-FLUORO-11-(1-ETHOXYCARBONYL-4-PIPERIDYLIDENE)-6,11-DIHYDRO-5H-BENZO[5,6]CYCLOHEPTA[1,2-b]PYRIDINE##STR79##

Stir a solution of the title compound of Preparative Example 2E above(5.0 g, 16.2 mmol) and triethylamine (2.6 g, 26 mmol) in dry toluene (60mL) at 80° C. under an argon atmosphere, and add ethylchloroformate (9.8g, 90 mmol) via a syringe. Stir the reaction at this temperature for 30minutes and at room temperature for one hour. Filter the reaction andremove the solvent. Pass the residue through a coarse SiO₂ column(60-200 mesh), and elute with CHCl₃ to yield the title compound as awhite solid. (4.5 g, Yield 76%, m.p. 112°-114° C. after trituration withpentane).

G.9-FLUORO-11-(4-PIPERIDYLIDENE)-6,11-DIHYDRO-5H-BENZO[5,6]CYCLOHEPTA[1,2-b]PYRIDINE##STR80##

Reflux the title compound of Preparative Example 2F above (3.83 g, 10.4mmol) with KOH (4.6 g) in 50 mL of ethanol/H₂ O (1:1) for 4 hours underan argon atmosphere. Pour the reaction mixture into a brine solution andextract with ethyl acetate (2×), dry over Na₂ SO₄ and filter. Remove thesolvent to give the title compound (2.86 g, Yield 90%, m.p. 138°-140°C.).

H. By employing the appropriately substituted benzyl halide listed inTable III in place of 4-fluorobenzyl chloride in step 2A above, thedesired products shown in the second column of Table III are prepared byemploying basically the same process as described in steps 2A-2G. Workuptime is determined by either TLC or HPLC. In some instances purificationof the product by chromatography is necessary.

                                      TABLE III                                   __________________________________________________________________________                 Product of Step G                                                 Benzyl Halide                                                                              ##STR81##         Melting Point                                 __________________________________________________________________________     ##STR82##   R.sup.3 = H, R.sup.4 = Cl                                                                       134-135° C..sup.a                        ##STR83##   R.sup.3 = H, R.sup.4 = F                                                                        138-140° C..sup.b                        ##STR84##   R.sup.3 = F, R.sup.4 = F                                                                        120-122° C..sup.b                        ##STR85##   R.sup.3 = H, R.sup.4 = H                                                                        123-124° C..sup.                        __________________________________________________________________________     .sup.a Recrystallized from ethyl acetate and pentane.                         .sup.b Triturated with pentane.                                          

PREPARATIVE EXAMPLE 3

A.6,11-Dihydro-11-(1-methyl-4-piperidylidene)-5H-benzo[5,6]cyclohepta[1,2-c]pyridine

The compound 5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-c]pyridine-11-one,may be prepared by following the methods described in U.S. Pat. No.3,419,565. This ketone may be converted to the title compound by themethods previously described in Preparative Example 2, steps D and E.

B.11-(1-Cyano-4-piperidylidene)-6,11-DIHYDRO-5H-benzo[5,6]cyclohepta[1,2-c]pyridine##STR86##

To a solution of 400 mg (1.35 mmole) of11-(1-methyl-4-piperidylidene)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-c]pyridinein 5.0 mL of benzene at room temperature and under an argon atmospherewas added dropwise a solution of 168 mg (1.59 mmole) of cyanogen bromidein 4 mL of benzene. After 30 min. the mixture was poured into water andextracted once with EtOAc. The organic layer was isolated, washed oncewith brine, dried over Na₂ SO₄, filtered, and concentrated in vacuo. Theresidue was purified via flash chromatography [21/2% MeOH in CH₂ Cl₂ ]to give 150 mg (37%) of the title compound as a solid: m.p. 212°-214° C.

C.11-(4-piperidylidene)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-c]pyridine##STR87##

A mixture of 140 mg (0.46 mmole) of11-(1-cyano-4-piperidylidene)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2c]pyridinein 20 mL of 30% aqueous HCl was refluxed for about 221/2 hrs. Themixture was poured into ice water, basified with 25% aqueous NaOH, andextracted twice with CH₂ Cl₂. The combined organic portions were driedover Na₂ SO₄, filtered, and concentrated in vacuo. The product waspurified via flash chromatography [5% MeOH saturated with NH₃ in CH₂ Cl₂] to give 95 mg (75%) of the title compound as a glass.

PREPARATIVE EXAMPLE 4

A. 8-Chloro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-one ##STR88##

Reflux a mixture of8-chloro-5,6-dihydro-1H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-one (25.99g, 0.107 mol.), recrystallized N-bromosuccinimide (21.35 g, 0.120 mol)and 167 mg (0.102 mmol) of azobisisobutyrylnitrile in 400 mL ofcarbontetrachloride under an argon atmosphere for 1.25 hours. Cool thesolution slowly to 50° C. and filter off the resultant precipitate.

Reflux the precipitate with 1,8-diazabicyclo[5.4.0]undec-7-ene ("DBU")(20 mL, 0.134 mol) in CH₂ Cl₂ (400 mL) for 1 hour. Wash with water (3×),dry over magnesium sulfate, filter and concentrate in vacuo.Recrystallize the crude product from CH₂ Cl₂ /toluene to give the titlecompound as colorless needles (8.93 g, yield 35%).

B.8-Chloro-11-(1-methyl-4-piperidinyl)-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ol##STR89##

To a mixture of 22 mL of 0.5M Grignard reagent ofN-methyl-4-chloropiperidiene (11.0 mmole) in THF at -45° C. and under anitrogen atmosphere was added dropwise over 15 min. a solution of 1.06gm (4.39 mmole) of8-chloro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-one in 23 mL of dryTHF. After 2 hr. 40 min. the reaction mixture was poured into water andextracted three times with EtOAc. The organic portions were combined,washed two times with brine, dried over MgSO₄, filtered, andconcentrated in vacuo. The residue was purified via flash chromatography[10% MeOH in CH₂ Cl₂ ] to give 970 mg (65%) of the title compound as aglass.

C.8-Chloro-11-(1-methyl-4-piperidilidene)-11H-benzo[5,6]cyclohepta[1,2-b]pyridine##STR90##

A mixture of 847 mg (2.48 mmole) of8-chloro-11-(1-methyl-4-piperidinyl)-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-olin 5 mL of concentrated sulfuric acid and 5 mL of trifluoromethanesulfonic acid was heated at 70° C. for 4 hr 10 min. The mixture wascooled to room temperature, poured into ice cold 30% aqueous KOH, andextracted three times with CH₂ Cl₂. The organic portions were combined,washed once with water, dried over MgSO₄, filtered, and concentrated invacuo to yield 755 mg (94%) of the title compound as a glass.

D.8-Chloro-11-[1-(2,2,2-trichloroethoxycarbonyl)-4-piperidylidene)-11H-benzo[5,6]cyclohepta[1,2-b]pyridine##STR91##

To a mixture of 755 mg (2.34 mmole) of8-chloro-11-(1-methyl-4-piperidylidene)-11H-benzo[5,6]cyclohepta[1,2-b]pyridineand 1.5 mL of triethylamine in 25 mL of dry toluene at room temperatureand under a nitrogen atmosphere was added 650 mL (4.72 mmole) of2,2,2-trichloroethyl chloroformate. The mixture was then heated to 90°C. Additional amounts of the chloroformate (500 mL and 300 mL) andtriethylamine (1.0 mL each time) were added to the mixture after 2 hr.and 3 hr. 40 min., respectively. After a total reaction time of 5 hr.the mixture was poured into water and extracted three times with CH₂Cl₂. The combined organic portions were dried over MgSO₄, filtered andconcentrated in vacuo. The residue was purified via flash chromatography[11/2% MeOH in CH₂ Cl₂ ] to afford 639 mg (56%) of the title compound asa glass.

E.8-Chloro-11-(4-piperidylidene)-11H-benzo[5,6]cyclohepta[1,2-b]pyridine##STR92##

A mixture of 210 mg (0.434 mmole) of8-chloro-11-[1-(2,2,2-trichloroethoxycarbonyl)-4-piperidylidene)-11H-benzo[5,6]cyclohepta[1,2-b]pyridineand 526 mg (8.05 mmole) of zinc dust in 4 mL of acetic acid was heatedat 60°-70° C. After 2 hr. 20 min. another 547 mg (8.37 mmole) of zincdust was added. After another 30 min. the mixture was basified with 10%aqueous NaOH and extracted four times with CH₂ Cl₂. The combined organicportions were washed once with water, dried over MgSO₄, filtered, andconcentrated in vacuo. The residue was purified via flash chromatography[5-6% MeOH/NH₃ in CHCl₃ ] to yield 71 mg (53%) of the title compound asa glass.

PREPARATIVE EXAMPLE 5

A. 5-Methoxy-8-chloro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-one

B. 6-Methoxy-8-chloro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-one##STR93##

Add Br₂ (5.10 mL, 99 mmol) to a mixture of8-chloro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-one (8.15 g, 33.7mmol) and powdered AgNO₃ (23.19 g, 137 mmol) in 300 mL of dry methanolat room temperature under an argon atmosphere. After 8 hours, addadditional AgNO₃ (5.90 g, 34.7 mmol) followed by additional Br₂ (1.7 mL,33.0 mmol). After 0.5 hours pour the mixture into water and extract (4×)with CH₂ Cl₂. Combine the organic phases, dry over magnesium sulfate,filter and concentrate in vacuo to give a mixture of the crude bromoethers.

Dissolve the crude product in CH₂ Cl₂ (200 mL) at room temperature andplace under an argon atmosphere. Add DBU (20 mL, 134 mmol) and refluxfor 1.3 hours. Add additional DBU (10 mL, 67 mmol) and reflux themixture for an additional hour. Pour the mixture into water and extract(3×) with CH₂ Cl₂. Combine the organic phases, wash with water and dryover magnesium sulfate. Filter and concentrate in vacuo. The twoisomeric vinyl ethers, title compounds A and B, are separated via flashchromatography [40%-75% ethyl acetate in hexanes] and recrystallize fromethyl acetate hexanes to give title compound A (1.51 g, 14.3%, mp 156°to 158° C.) and title compound B (3.68 g, 35%, mp 161° to 162° C.).

C.5-Methoxy-8-chloro-11-(1-methyl-4-Piperidinyl)-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ol##STR94##

Add a 1.5M Grignard solution of N-methyl 4-chloropiperidine (150 mL,22.5 mmol) in THF dropwise over a 7 minute period to5-methoxy-8-chloro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-one (5.00g, 18.4 mmol) in THF (70 mL) at 0° C. and under an argon atmosphere.Quench the reaction after 30 minutes with a saturated solution of NH₄ Cl(pH 8) and extract (3×) with CHCl₃. Combine the organic portions, washwith brine, dry over sodium sulfate, filter and concentrate in vacuo.Purify via flash chromatography (CH₃ OH 5% in CH₂ Cl₂) to give the titlecompound (3.60 g, 53%) as a solid. The solid may be recrystallized fromisopropyl ether to give a white powder (mp 168°-170° C.).

D.8-Chloro-11-(1-methyl-4-piperidylidene)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridin-5-one##STR95##

Dissolve5-Methoxy-8-chloro-11-(1-methyl-4-piperidinyl)-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ol(4.26 g) in CH₃ OH (6 mL) at 0° C. under an argon atmosphere. Add slowlya cooled solution of 92% aqueous H₂ SO₄ (54 mL). Allow the mixture towarm to room temperature for 35 minutes. Pour the solution onto ice,basify with aqueous NaOH (25%), and extract with methylene chloride(3×). Combine the organic portions, wash with brine and dry over sodiumsulfate. Filter and concentrate in vacuo. Triturate the residue withispropyl ether to give an intermediate,8-chloro-11-hydroxy-11-(1-methyl-4-piperidinyl)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridin-5-oneas a white solid (3.58 g., 92%, m.p. 170° to 174° C. as HCl salt).

Dissolve the intermediate compound (3.58 g, 10.0 mmol) intrifluoromethane sulfonic acid (50 mL) and heat to 45° C. under an argonatmosphere for 3 hours. Pour the mixture onto ice, basify with aqueousNaOH (25% w/v), and extract with CHCl₃ (3×). Combine the organicportions, wash with brine and dry over sodium sulfate. Filter andconcentrate in vacuo. Chromatograph on silica gel (5% CH₃ OH in CH₂ Cl₂)to give the title compound as an off white solid (1.703 g, 50%, 58%based on recovered starting material). An analytical sample was preparedby recrystallization of the product with ethyl acetate/isopropyl ether(mp 162°-163° C.).

E.Ethyl-4-(8-chloro-5-ethoxycarbonyloxy-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)-1-piperidinecarboxylate ##STR96##

Dissolve the8-Chloro-11-(1-methyl-4-piperidylidene)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridin-5-one(617 mg, 1.82 mmol) and triethylamine (0.50 mL, 3.58 mmol) in toluene(12 mL) at 80° C. under an argon atmosphere. Add dropwise over 2 minutesethyl chloroformate (0.87 mL, 9.10 mmol). After 25 minutes cool themixture to room temperature, filter, and concentrate in vacuo. Purifythe crude product via flash chromatography (1% CH₃ OH in CH₂ Cl₂) toyield the title compound as a glass (834 mg, 98%).

F.8-Chloro-11-(4-piperidylidene)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridin-5-one##STR97##

Mix ethyl4-(8-chloro-5-ethoxycarbonyloxy-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)-1-piperidinecarboxylate (897 mg, 1.91 mmol) and aqueous KOH (20 mL, w/v) in ethanol(15 mL) and reflux under an argon atmosphere for 25 hours. Pour themixture into water and extract with CHCl₃ (3×). Combine the organicportions, wash with brine, dry over sodium sulfate, filter, andconcentrate in vacuo. Purify the residue via flash chromatography (2%CH₃ OH saturated with NH₃ in CH₂ Cl₂) and triturate with isopropyl etherto give the title compound as a white solid (417 mg, 67%, mp 194°-196°C. (dec)).

G.5-Hydroxy-8-chloro-11-(4-piperidylidene)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine##STR98##

Mix8-Chloro-11-(4-piperidylidene)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridin-5-one(400 mg, 1.23 mmol) in CH₃ OH (20 mL) at 0° C. under an argonatmosphere, and add in 3 portions NaBH₄ (total 231 mg, 6.10 mmol). After30 minutes, pour the mixture into water and extract (3×) with ethylacetate. Combine the organic portions, wash with brine, dry over sodiumsulfate, filter and concentrate in vacuo. Triturate the solid withisopropyl ether/ethyl acetate to give the title compound as a whitesolid (351 mg, 87%).

PREPARATIVE EXAMPLE 68-CHLORO-11(Z)-2,5-DIMETHYL-4-PIPERIDYLIDENE)-6,11-DIHYDRO-5H-BENZO[5,6]CYCLOHEPTA[1,2-b]PYRIDINE

A. 1,2,6-trimethyl-4-chloropiperidine ##STR99##

The starting material, 1,2,6-trimethyl-4-piperidinol, may be prepared bythe method disclosed in Archi Kern, Volume 27, pages 189-192 (1955). Toa cooled (ice-bath) solution of 1,2,6-trimethyl-4-piperidinol (12.2 g,85.3 mmol) in 120 mL of dry benzene was slowly added thionylchloride (17mL, 233 mmole). The dark reaction mixture was then warmed to 70° C. for20 min. The reaction was cooled and then suspended in water followed byfiltration. The filtrate was extracted once with diethylether. Theaqueous layer was separated and then basified with 30% NaOH solution.The product was then extracted twice with CH₂ Cl₂, washed once withbrine, dried (Na₂ SO₄), filtered and solvent removed to give a crudebrown liquid which was distilled (2-4 mmHg, 62°-64° C.) to give thetitle compound (8.0 g, 58% yield).

B.8-chloro-11-(1,2,6-trimethyl-4-piperidinyl)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ol##STR100##

The chloride, 1,2,6-trimethyl-4-chloropiperidine, (4.2 g, 26 mmol) wasslowly dripped into a solution of dry THF (18 mL) containing Mg (633 mg,26.3 mm). The Grignard reagent was then formed after heating for 6 hoursat 70° C.

To a cooled (ice-bath), stirred solution of8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-one (6.3g, 26 mmol) in THF (50 mL) was added the above Grignard reagent. Thereaction was allowed to stir for 1 hr. at this temperature and thenquenched with NH₄ Cl solution. The product was extracted 3× with EtOAc,washed once with brine, dried (Na₂ SO₄), filtered and solvent removed togive a crude brown material which was chromatographed to give the titlecompound (5.1 g, 53% yield) as a yellowish glass.

C.8-chloro-11-(1-methyl-(Z)-2,6-dimethyl-4-piperidylidene)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine##STR101##

A mixture of8-chloro-11-(1,2,6-trimethyl-4-piperidinyl)-6,11-dihydro-5H-benzo[5,6]-cyclohepta[1,2-b]pyridin-11-ol(5.0 g, 14.1 mmol) in 85% H₂ SO₄ (100 mL) was heated in an oil bath(60°-65° C.) for 3 hours. The reaction was cooled and diluted with waterfollowed by basification with 25% aq. NaOH solution. The crude productwas extracted with CH₂ Cl₂, washed with brine, dried (Na₂ SO₄), filteredand solvent removed. Purification and separation of the E and Z isomersvia chromatography (2%→5% MeOH saturated with NH₃ in CH₂ Cl₂) gave thetitle compound (300 mg, 6%).

D.8-chloro-11-(1-cyano-(Z)-2,6-dimethyl-4-piperidylidene)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine##STR102##

A solution of 300 mg (0.85 mmol) of8-chloro-11-(1-methyl-(Z)-2,6-dimethyl-4-piperidylidene)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridinein benzene (4.5 mL) was slowly dripped into a stirred solution of BrCN(133 mg, 1.2 mmol) in benzene (4.5 mL) at room temperature. This wasallowed to stir for 21/2 hr under argon. The reaction mixture wassuspended between water and EtOAc. The EtOAc layer was washed with brineand dried (NaSO₄). After filtration the solvent was removed and thecrude material was chromatographed (3% MeOH in CH₂ Cl₂) to give thetitle compound (251 mg, 81% yield).

E.8-chloro-11-((Z)-2,6-dimethyl-4-piperidylidene)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine##STR103##

A mixture of8-chloro-11-(1-cyano-(Z)-2,6-dimethyl-4-piperidylidene)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine (200 mg, 0.55 mmol) in 80% HCl (20 mL) wasallowed to reflux for 7 hours. The mixture was cooled and then basifiedwith 25% NaOH. The product was extracted 2× with CH₂ Cl₂, separated,washed once with brine, dried (NaSO₄), filtered and solvent removed togive the title compound (174 mg, 93% yield) as a white glass.

F. By following similar procedures in steps D & E above,8-chloro-11-(1-methyl-(E)-2,6-dimethyl-4-piperidylidene)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridinewas converted to8-chloro-11-((E)-2,6-dimethyl-4-piperidylidene-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine.

PREPARATIVE EXAMPLE 78-CHLORO-11-(4-PIPERIDYLIDENE)-6,11-DIHYDRO-3-METHYL-5H-BENZO[5,6]CYCLOHEPTA[1,2-b]PYRIDINE

A. 3,5-DIMETHYLPYRIDINIUM N-OXIDE ##STR104##

A solution of 285 mL (1.31 mol) of 35% peracetic acid was slowly addedto a stirred solution of 149 g (1.39 mol) of 3,5-dimethylpyridine duringwhich the temperature rose to 85° C. and was maintained at thistemperature during addition. After the temperature of the mixturedropped to about 35° C. the reaction was stored at 5° C. overnight.

After partial removal of 185 ml of acetic acid via distillation undervacuum, the reaction was washed with NaHSO₄ solution and thenneutralized with 10% NaOH solution to pH of about 7. The product wasextracted with CH₂ Cl₂ to give the title compound as a white solid(yield 142 g, 83%).

B. 1-METHOXY-3,5-DIMETHYLPYRIDINIUM METHYL SULFATE ##STR105##

Dimethylsulfate (42.0 g, 0.33 mol) was slowly added to a mechanicallystirred solids of 41.0 g (0.33 mol) of 3,5-dimethylpyridinium N-oxide.The mixture was then heated on a steam bath for 1 hr. Then vacuum wasapplied while cooling to give a brownish solid of the title compound inquantitative yield.

C. 2-CYANO-3,5-DIMETHYLPYRIDINE ##STR106##

To a cooled (0° C.) solution of sodium cyanide (49.0 g, 0.999 mol, 3.0eq.) in 135 mL of water (air free) was dripped 1-methoxy-3,5-dimethylpyridinium methyl sulfate (83.0 g, 0.33 mol) in 100 mL water (air free)in 11/4 hr., keeping the temperature below 3° C. The reaction mixturewas stored at about 3° C. overnight. The mixture was filtered and washedwith water to give 40 g of the title compound. An analytical sample wasrecrystallized from isopropyl ether and pentane (4:1) (m.p. 61°-62° C.).

D. N-(11-dimethylethyl)-3,5-dimethyl-2-pyridine carboxamide ##STR107##

To a stirred solution of 20.3 g (0.153 mol) of2-cyano-3,5-dimethylpyridine in 100 mL of acetic acid was added 20 mL ofconc. sulfuric acid within 10 minutes (temp. rose to 35° C.), followedby 20 mL of t-butanol over an additional 15 minutes. The solution waswarmed at 75° C. for 30 minutes after which it was cooled to roomtemperature and basified with 25% NaOH. The product was extracted 3×with EtOAc (600 mL), which was combined and washed 1× with brine, dried(Na₂ SO₄), filtered and concentrated in vacuo to give the title compound(31.26 g) as a yellowish oil.

E.8-Chloro-11-(4-piperidylidene)-6,11-dihydro-3-methyl-5H-benzo[5,6]cyclohepta[1,2-b]pyridine

By substituting in step 1B aboveN-(1,1-dimethylethyl)-3,5-dimethyl-2-pyridine carboxamide forN-(1,1dimethylethyl)-3-methyl-2-pyridine carboxamide and employingbasically the same methods as steps B through G, one obtains8-chloro-11-(4-piperidylidene)-6,11-dihydro-3-methyl-5H-benzo[5,6]cyclohepta[1,2-b]pyridine.Reaction times are determined by TLC or HPLC.

PREPARATIVE EXAMPLE 811-(4-PIPERIDYL)-6,11-DIHYDRO-5H-BENZO[5,6]CYCLOHEPTA[1,2-b]PYRIDINE

A. (1-Methyl-4-piperidinyl)[3-(2-phenylethyl)-2-pyridinyl]methanol##STR108##

To a mixture of 5.0 g (16.2 mmole) of(1-methyl-4-piperidinyl)[3-(2-phenylethyl)-2-pyridinyl]methanone (whichcan be prepared in the same manner as described in Preparative Example1, Steps A-D) in 70 mL of methanol was added portionwise 0.8 g (21.1mmole) of sodium borohydride. The next day the solution was concentratedin vacuo to give a slurry which was dissolved in water and extractedwith CHCl₃. The combined organic portions were dried over MgSO₄,filtered, and concentrated in vacuo to provide a liquid which wasdistilled (bp 190°-195° C. 1 mm Hg) to give 4.4 gms of the titlecompound as a viscous oil.

B.11-(1-Methyl-4-piperidyl)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine##STR109##

A mixture of 3.5 gm (11.3 mmole) of4-(1-methylpiperidyl)-2-[3-(2-phenylethyl)pyridyl]methanol and 200 g ofpolyphosphoric acid was heated between 160°-170° C. for 13 hours. Themixture was cooled to room temperature, poured into water, basified withaqueous NaOH and extracted with ether. The combined organic portionswere concentrated in vacuo and the product recrystallized to give thetitle compound as a white solid, (mp 111°-114° C.).

C. In a similar manner to that described in Example 1, Steps F-G,11-(1-methyl-4-piperidyl)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridinecan be converted to11-(4-piperidyl)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine.

EXAMPLE 18-CHLORO-11-(1-METHOXYACETYL-4-PIPERIDYLIDENE)-6,11-DIHYDRO-5H-BENZO[5,6]CYCLOHEPTA[1,2-b]PYRIDINE##STR110##

Dissolve the title compound of Preparative Example 1G above,8-chloro-11-(4-piperidylidene)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine(3.00 gm, 9.7 mmol) and 1.2 mL (14.8 mmol) of pyridine in dry methylenechloride (20 mL) at 0° C. under an argon atmosphere. Add methoxyacetylchloride (1.1 mL, 12.0 mmol) dropwise, and slowly warm to roomtemperature. After 1.5 hours take up the mixture in methylene chlorideand wash with brine. Dry over Na₂ SO₄, filter, and concentrate in vacuoto give a residue and purify via flash chromatography. Triturate theproduct with pentane and recrystallize from ethyl acetate/pentane togive the title compound as a white solid. (1.89 g, m.p. 104°-106° C.).

EXAMPLE 2 8 OR9-SUBSTITUTED-11-(1-SUBSTITUTED-4-PIPERIDYLIDENE)-6,11-DIHYDRO-5H-BENZO[5,6]CYCLOHEPTA[1,2-b]PYRIDINECOMPOUNDS

By substituting the acid halide and amine listed in the first and secondcolumns, respectively, of Table IV below for the methoxyacetyl chlorideand compound of Preparative Example 1G, respectively in the processdescribed in Example 1 above, the product compounds listed in the thirdcolumn of Table IV were prepared. Workup times were determined bymonitoring the reaction by TLC. Reaction times and temperatures varyslightly. In some instances purification of the product bychromatography was not necessary.

                                      TABLE IV                                    __________________________________________________________________________     ##STR111##                                                                                                   ##STR112##                                                                   (R.sup.3 and R.sup.4 same                                                                         Product                    Acid Halide                    as in Amine)        Melting                                                                              Com-                ClCOR, R = R.sup.3   R.sup.4   R =        Z =      Point                                                                                mentsee.C.          __________________________________________________________________________    C.sub.6 H.sub.5                                                                          Cl        H         C.sub.6 H.sub.5                                                                          O        --     glassy                                                                        solid               CH.sub.3   Cl        H         CH.sub.3   O        155-157°                                                               C..sup. a                  C(CH.sub.3).sub.3                                                                        Cl        H         C(CH.sub.3).sub.3                                                                        O        158-160°                                                               C..sup.b                   CH.sub.2 C(CH.sub.3).sub.3                                                               Cl        H         CH.sub.2 C(CH.sub.3).sub.3                                                               O        137-139°                                                               C..sup.b                    ##STR113##                                                                              Cl        H                                                                                        ##STR114##                                                                              O        178-180°                                                               C..sup.b                   CO.sub.2 C.sub.2 H.sub.5                                                                 Cl        H         CO.sub.2 C.sub.2 H.sub.5                                                                 O        126-128°                                                               C..sup.c                    ##STR115##                                                                              Cl        H                                                                                        ##STR116##                                                                              O        136-138° C.         CH.sub.2 CH.sub.2 CH.sub.3                                                               Cl        H         CH.sub.2 CH.sub.2 CH.sub.3                                                               O        119-122°                                                               C..sup.d                   SC.sub.2 H.sub.5                                                                         Cl        H         SC.sub.2 H.sub.5                                                                         O        167.5- triturated                                                             168.5° C..sup.c                                                               from                                                                          pentane                                                                       after                                                                         flash                                                                         chroma-                                                                       tography            C.sub.2 H.sub.5                                                                          Cl        H         C.sub.2 H.sub.5                                                                          O        128-130°                                                               C..sup.a                   CH.sub.2 OC.sub.2 H.sub.5                                                                Cl        H         CH.sub.2 OC.sub.2 H.sub.5                                                                O        107-109°                                                                      triturated                                                                    from                                                                          isopropyl                                                                     ether                                                                         after                                                                         flash                                                                         chroma-                                                                       tography            CH(CH.sub.3)OCH.sub.3                                                                    Cl        H         CH(CH.sub.3)OCH.sub.3                                                                    O        128-130°                                                               C..sup.c,d                 C(O)CH.sub.3                                                                             Cl        H         C(O)CH.sub.3                                                                             O        150-152°                                                               C..sup.c                   CH.sub.2 OCH.sub.3                                                                       H         Cl        CH.sub.2 OCH.sub. 3                                                                      O        104-107°                                                               C..sup.c                   CH.sub.2 OCH.sub.3                                                                       CH.sub.3  H         CH.sub.2 OCH.sub.3                                                                       O        --     glassy                                                                        solid               CH.sub.2 OCH.sub.3                                                                       H         H         CH.sub.2 OCH.sub.3                                                                       O         87-89° C.          CH.sub.2 OCH.sub.3                                                                       F         H         CH.sub.2 OCH.sub.3                                                                       O        114-116°                                                               C..sup.c                   CH.sub.2 CH.sub.2 CH.sub.3                                                               F         H         CH.sub.2 CH.sub.2 CH.sub.3                                                               O        123-125°                                                               C..sup.c                   CH.sub.2 OCH.sub.3                                                                       H         F         CH.sub.2 OCH.sub.3                                                                       O        113-115°                                                               C..sup.c                   CH.sub.3   H         F         CH.sub.3   O        --     glassy                                                                        solid               CH.sub.3   F         H         CH.sub.3   O        --     glassy                                                                        solid               CH.sub.2 OCH.sub.3                                                                       F         F         CH.sub.2 OCH.sub.3                                                                       O        151-152°                                                               C..sup.c                   C(O)CH.sub.3                                                                             Cl        H         CH(OH)CH.sub. 3.sup.e                                                                    O        --     glassy                                                                        solid               C.sub.6 H.sub.5                                                                          Cl        H         C.sub.6 H.sub.5                                                                          S        147-150°                                                               C..sup.f                                                                             .sup.g              CH.sub.3   CH.sub.3  H         CH.sub.3   O        --     glassy                                                                        solid               CH.sub.3   Cl        Cl        CH.sub.3   O        177-179° C.         CH.sub.3   Cl        H         CH.sub.3   S        153-155°                                                                      .sup.g              CH.sub.3   OCH.sub.3 H         CH.sub.3   O        --     glassy                                                                        solid               CH.sub.3   H         Cl        CH.sub.3   O        --     glassy                                                                        solid               CH.sub.3   F         F         CH.sub.3   O        188-189° C.         CH.sub.3   H         H         CH.sub.3   O        155-156° C.          ##STR117##                                                                              H         H                                                                                        ##STR118##                                                                              O        207-208° C.          ##STR119##                                                                              H         H                                                                                        ##STR120##                                                                              O        157-158° C.          ##STR121##                                                                              H         H                                                                                        ##STR122##                                                                              O        138-141° C.         CH.sub.3   Br        H         CH.sub.3   O        165-166° C.         CH.sub.3                                                                                  ##STR123##         CH.sub.3   O        160-162° C.         CH.sub.2 CHCH.sub.2                                                                      Cl        H         CH.sub.2 CHCH.sub.2                                                                      O        157-158° C.         C(CH.sub.3).sub.2 OCH.sub.3                                                              Cl        H         C(CH.sub.3).sub.2 OCH.sub.3                                                              O        147-149° C.         CHCl.sub.2 Cl        H         CHCl.sub.2 O        153-155° C.         CH.sub.3                                                                                  ##STR124##                                                                                        ##STR125##         --     white glass         CH.sub.3                                                                                  ##STR126##                                                                                        ##STR127##         103-106°                                                                      glass               CH.sub.3                                                                                  ##STR128##                                                                                        ##STR129##         --     glass following                                                               xidation with                                                                 PDC in CH.sub.2                                                               Cl.sub.2            CH.sub.3                                                                                  ##STR130##                                                                                        ##STR131##         177-179° C.         CH.sub.2 OCH.sub.3                                                                        ##STR132##                                                                                        ##STR133##         --     glass               __________________________________________________________________________     .sup.a Recrystallized form acetone and pentane.                               .sup.b Recrystallized from ethylacetate and isopropylether.                   .sup.c Recrystallized from ethylacetate and pentane.                          .sup.d Recrystallized from isopropyl ether.                                   .sup.e Following reduction with NaBH.sub.4 in methanol.                       .sup.f Recrystallized with ethylacetate and diethylether.                     .sup.g The ZO compound produced is converted to the ZS compound by a          conventional sulfuration reaction employing Lawesson's reagent.          

EXAMPLE 38-CHLORO-11-(1-ACETYL-4-PIPERIDYLIDENE)-6,11-DIHYDRO-5H-BENZO[5,6]CYCLOHEPTA[1,2-b]PYRIDINE##STR134##

An alternate method of making the title compound is to dissolve thetitle compound of Preparative Example 1G (3.02 g., 9.72 mmole) andpyridine (3.9 mL, 48.1 mmol) in dry methylene chloride (40 mL) at 0° C.under an argon atmosphere and add dropwise acetic anhydride (4.5 mL,47.7 mmole). Slowly warm the reaction mixture to room temperature. After2 hours, take up the mixture in methylene chloride, wash with water (2×)and with brine. Dry the mixture over sodium sulfate, filter andconcentrate in vacuo to give a product which is recrystallized fromacetone and pentane to give the title compound as a white solid. (2.41gm, m.p. 155°-157° C.).

EXAMPLE 4 8 OR9-SUBSTITUTED-11-(1-SUBSTITUTED-4-PIPERIDYLIDENE)-6,11-DIHYDRO-5H-BENZO[5,6]CYCLOHEPTA[1,2-b]PYRIDINECOMPOUNDS

By substituting the acid anhydride and amine listed in the first andsecond columns, respectively, of Table V below for the acetic anhydrideand compound of Preparative Example 1G, respectively in the processdescribed in Example 3 above, the product compounds listed in the thirdcolumn of Table V were prepared. Workup times were determined bymonitoring the reaction by TLC. Reaction times and temperatures varyslightly. In some instances purification of the product bychromatography was not necessary.

                                      TABLE V                                     __________________________________________________________________________     ##STR135##                                                                                             ##STR136##                                                                   (R.sup.3 and R.sup.4 same                                                                      Product                             Acid Anhydride           as in Amine)     Melting Point                       O(COR).sub.2 R =                                                                      R.sup.3  R.sup.4 R =      Z =     °C.                                                                           Comments                     __________________________________________________________________________    CH.sub.3                                                                              R.sup.3 = Cl                                                                            R.sup.4 = H                                                                          R = CH.sub.3                                                                           Z = O   --     glass                                R.sup.5 = H,                                                                  R.sup.6 = CH.sub.3                                                            X = N                                                                 CH.sub.3                                                                              R.sup.3 = Cl                                                                           R.sup.4 = H                                                                           R = CH.sub.3                                                                           Z = O   --     glass, no                            R.sup.5 = R.sup.6 = CH.sub.3             pyridine was                         X = N                                    employed in                                                                   alkylation                   CH.sub.3                                                                              R.sup.3 = R.sup.4 = H                                                                          R = CH.sub.3                                                                           Z = O   --     glass                                R.sup.5 = R.sup.6 = H                                                         X = CH                                                                CH.sub.3                                                                               ##STR137##                                                                                     ##STR138##      112-115° C.                  CF.sub.3                                                                               ##STR139##                                                                                     ##STR140##      142-144° C.                  __________________________________________________________________________

EXAMPLE 58-CHLORO-11-(1-ACETYL-(Z)-2,6-DIMETHYL-4-PIPERIDYLIDENE)-6,11-DIHYDRO-5H-BENZO[5,6]CYCLOHEPTA[1,2-b]PYRIDINE##STR141##

To a solution of8-chloro-11-(1-acetyl-(Z)-2,6-dimethyl-4-piperidylidene)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine(50 mg, 0.147 mmol) and N,N-dimethylaminopyridine (24 mg, 0.19 mmol) indry CH₂ Cl₂ (2.6 mL) was added acetic anhydride (60 μl, 0.63 mmol). Thereaction was stirred for 16 hours. The reaction was quenched with waterand then diluted Na₂ CO₃ solution. The product was extracted with CH₂Cl₂ and washed with brine, dried (Na₂ SO₄), filtered and solvent removedto give a crude product which was isolated from preparative TLC plates(eluted with 5% MeOH in CHCl₃) to give the title compound (42 mg).

By a similar procedure8-chloro-11-(1-acetyl-(E)-2,6-dimethyl-4-piperidylidene)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridinewas prepared.

EXAMPLE 68-CHLORO-11-[1-(ETHOXYCARBONYLMETHYL)-4-PIPERIDYLIDENE]-6,11-DIHYDRO-5H-BENZO[5,6]CYCLOHEPTA[1,2-b]PYRIDINE##STR142##

Dissolve the title compound of Preparative Example 1G (3.0 g., 9.7 mmol)in triethylamine (2.0 mL, 14.3 mmol), toluene (20 mL) andtetrahydrofuran (10 mL) at room temperature under an argon atmosphere.Add dropwise ethyl bromoacetate (1.30 mL, 11.7 mmol). After 1.5 hours,filter the mixture and concentrate in vacuo. Purify the residue viaflash chromatography. Triturate the product with pentane andrecrystallize from isopropyl ether to give the title compound as a whitesolid. (2.5 gins, Yield 65%, m.p. 80°-82° C.).

EXAMPLE 7

Substitute the appropriate halide and amine from Table VI below into theprocess of Example 6 to yield the product compounds listed in column 3of Table VI. The completion time for the reaction is determined bymonitoring the reaction by TLC. The reaction time and temperature varyslightly. In some instances purification of the product bychromatography is not necessary.

                                      TABLE VI                                    __________________________________________________________________________     Halide ClCH.sub.2 R R =                                                                          ##STR143##                                                                                      ##STR144##          Comments            __________________________________________________________________________    CH.sub.2 OCH.sub.2 CH.sub.2 OH                                                                   R.sup.3 = Cl, R.sup.4 = H                                                                       R.sup.3 = Cl, R.sup.4 = H, Z =                                                H.sub.2             glassy                                                    R = CH.sub.2 OCH.sub.2 CH.sub.2                                                                   solid.sup.a           ##STR145##        R.sup.3 = Cl, R.sup.4 = H,                                                                       ##STR146##         glassy solid.sup.                                                             b                    __________________________________________________________________________     .sup.a Reaction utilizes KI and K.sub.2 CO.sub.3 in toluene; Reflux 8         hours.                                                                        .sup.b Obtained by reduction of the precursor ketone with NaBH.sub.4 in       methanol.                                                                

EXAMPLE 88-CHLORO-11-[1-(t-BUTOXYCARBONYLAMINOACETYL)-4-PIPERIDYLIDENE]-6,11-DIHYDRO-5H-BENZO[5,6]CYCLOHEPTA[1,2-b]PYRIDINE##STR147##

Dissolve N-t-butoxycarbonylglycine (1.84 g, 10.5 mmol),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (DEC) (2.80g, 14.6 mmol), 1-hydroxybenzotriazole hydrate (HOBT) (1.98 g, 14.7mmol), in triethylamine (Et₃ N) (2.0 mL, 14.3 mmol) and dry methylenechloride (30 mL) at 0° C. and under an argon atmosphere. Add dropwise asolution of the title compound from Preparative Example 1G (3.0 g., 9.7mmol) in dry methylene chloride (15 mL). After 1.5 hours, take up themixture in methylene chloride and wash with water and then with brine.Dry over sodium sulfate, filter and concentrate in vacuo to give an oilwhich is purified with flash chromatography (5% MeOH in CHCl₃).Recrystallize the purified product from ethyl acetate and pentane togive the title compound as a white solid. (4.15 gm, m.p. 209°-211° C.).

EXAMPLE 98-CHLORO-11-(1-AMINOACETYL-4-PIPERIDYLIDENE)-6,11-DIHYDRO-5H-BENZO[5,6]CYCLOHEPTA[1,2-b]PYRIDINE##STR148##

Mix the title compound of Example 8 (2.50 g., 5.34 mmol) in a saturatedhydrogen chloride solution in dioxan (35 mL), and stir at roomtemperature under an argon atmosphere overnight. Concentrate the mixturein vacuo and triturate the resultant gummy product with ethanol anddiethylether to give the title compound as white solid. (2.28 g.)

EXAMPLE 108-CHLORO-11-(1-FORMYL-4-PIPERIDYLIDENE)-6,11-DIHYDRO-5H-BENZO[5,6]CYCLOHEPTA[1,2-b]PYRIDINE##STR149##

Dissolve the title compound of Preparative Example 1G (5.0 g., 16.1mmol) in 100 mL of ethyl formate and reflux the mixture for 4 hours.Concentrate the mixture in vacuo and triturate the product with hexaneto give the title compound as a white solid (2.2 gm, m.p. 147°-149° C.).

EXAMPLE 118-CHLORO-11-(1-METHYLAMINOCARBONYL-4-PIPERIDYLIDENE)-6,11-DIHYDRO-5H-BENZO[5,6]CYCLOHEPTA[1,2-b]PYRIDINE##STR150##

To a mixture of 2.03 g (6.53 mmole) of8-chloro-11-(1-acetyl-4-piperidylidene)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridineand 1.0 mL of triethylamine in 30 mL of dry THF at -10° C. and under anitrogen atmosphere was added dropwise over 10 minutes 0.40 mL (6.78mmole) of methylisocyanate. The mixture was slowly warmed to roomtemperature. After 4 hours it was poured in water and extracted 3× withCH₂ Cl₂. The organic portions were combined, dried over MgSO₄, filteredand concentrated in vacuo to afford a product which was recrystallizedfrom CH₂ Cl₂ /ethyl acetate/hexanes to give 1.70 g of the title compoundas white crystals. (m.p. 194.5°-196° C.).

EXAMPLE 125-HYDROXY-8-CHLORO-11-(1-ACETYL-4-PIPERIDYLIDENE)-6,11-dihydro-5H-BENZO[5,6]CYCLOHEPTA[1,2-b]PYRIDINE##STR151##

To a mixture of 32.6 mg (0.10 mmole) of5-hydroxy-8-chloro-11-(4-piperidylidene)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridineand 9.7)1 (0.12 mmole) of pyridine in a solution of 2 mL of methanol and1 mL of CH₂ Cl₂ at 0° C. and under a nitrogen atmosphere was added 11.3)1 (0.12 mmole) of acetic anhydride. After 30 min. the mixture waspoured into water which was subsequently adjusted to pH of about 9 withaqueous sodium hydroxide. The mixture was extracted 2× with CH₂ Cl₂. Theorganic portions were combined, washed once with brine, dried over Na₂SO₄, filtered, and concentrated in vacuo to yield 31.2 mg of the titlecompound as a glass.

EXAMPLE 13N-METHYL-8-CHLORO-11-(1-ACETYL-4-PIPERIDYLIDENE)-6,11-DIHYDRO-5H-BENZO[5,6]CYCLOHEPTA[1,2-b]PYRIDINIUMIODIDE ##STR152##

A mixture of 500 mg (1.42 mmole) of8-chloro-11-(1-acetyl-4-piperidylidene)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridineand 175 μl (2.81 mmole) of methyl iodide in 30 mL of toluene was heatedat 100° C. for about 19 hours. The reaction mixture was cooled to roomtemperature and the solvent decanted off. The remaining residue wasrecrystallized twice from CH₂ Cl₂ /isopropyl ether/hexanes to give 432mg of the title compound as tan crystals. (m.p. 245°-247° C.).

EXAMPLE 148-CHLORO-11-(1-ACETYL-4-PIPERIDYLIDENE)-6,11-DIHYDRO-5H-BENZO[5,6]CYCLOHEPTA[1,2-b]PYRIDINE-N-OXIDE##STR153##

To a mixture of 711 mg (2.01 mmole) of8-chloro-11-(1-acetyl-4-piperidylidene)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridinein 30 ml of dry CH₂ Cl₂ at -10° C. and under a nitrogen atmosphere wasadded 246 mg (1.60 mmole) of m-chloroperoxybenzoic acid. After 95 min.the mixture was taken up in CH₂ Cl₂ and washed once with 10% aqueoussodium bisulfite and once with 10% aqueous sodium hydroxide. It wasdried over magnesium sulfate, filtered, and concentrated in vacuo. Theproduct was purified via flash chromatography (MeOH in CH₂ Cl₂) andrecrystallized from ethyl acetate/hexanes to give 175 mg of the titlecompound as a hemi-ethyl acetate solid. (m.p. 90.5°-93° C.)

In a similar manner8,9-difluoro-11-(1-acetyl-4-piperidylidene)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridinewas converted to8,9-difluoro-11(1-acetyl-4-piperidylidene)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine-N-oxide.

EXAMPLE 158-CHLORO-11-(1-ACETYL-4-PIPERAZINYL)-6,11-DIHYDRO-5H-BENZO[5,6]CYCLOHEPTA[1,2-b]PYRIDINE##STR154##

A mixture of 1.98 g (7.50 mmole) of8,11-dichloro-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine, 1.16g (9.05 mmole) of N-acetylpiperazine, and 2.0 mL of triethylamine in 20mL of dry THF was refluxed under a nitrogen atmosphere for 16 hr. It wasthen poured into 5% aqueous sodium hydroxide and extracted three timeswith methylene chloride. The combined organic portions were dried overMgSO₄, filtered and concentrated in vacuo to yield a product which waspurified by flash chromatography (5% CH₃ OH in CHCl₃) to afford 1.71 gof the title compound as a glass.

EXAMPLE 16

By employing the appropriately substituted piperazine listed in TableVII in place of N-acetyl piperazine the desired products were preparedunder basically the same conditions as described above. Workup time wasdetermined by TLC.

                                      TABLE VII                                   __________________________________________________________________________    Product                                                                        ##STR155##                                                                   Amine       Product      m.p.   Comments                                      __________________________________________________________________________     ##STR156##                                                                                ##STR157##  146-148° C.                                    ##STR158##                                                                                ##STR159##  glass  run at ambient temp, then reflux               ##STR160##                                                                                ##STR161##  glass  run at ambient temp., then reflux              ##STR162##                                                                                ##STR163##  143-146° C.                                                                   employed large excess (11 equiv.) of                                          piperazine with no Et.sub.3 N run at                                          ambient temp.                                  ##STR164##                                                                                ##STR165##  glass  piperazine was limiting                       __________________________________________________________________________                                    reagent                                   

EXAMPLE 178-CHLORO-11-[1-ACETYL-4-PIPERIDINYL]-11H-BENZO[5,6]CYCLOHEPTA[1,2-b]PYRIDIN##STR166##

A mixture of 1.17 g (3.32 mmol) of8-chloro-(1-acetyl-4-piperidylidene)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridinein 4 mL of trifluoromethane sulfonic acid was heated between 180°-200°C. for 3 days under a nitrogen atmosphere. The mixture was cooled toroom temperature, poured into 10% aqueous sodium hydroxide and extractedthree times with CH₂ Cl₂. The organic portions were combined, dried overMgSO₄, filtered, and concentrated in vacuo. The residue was purified viaflash chromatography [5% MeOH in CH₂ Cl₂ ] to give 534 mg of the titlecompound as a glass.

The following are examples of pharmaceutical dosage forms which containa compound of the invention. As used therein, the term "active compound"is used to designate the compound8-chloro-11-(1-acetyl-4piperidylidene)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine.The scope of the invention in its pharmaceutical composition aspect isnot to be limited by the examples provided, since any other compound ofstructural formula I can be substituted into the pharmaceuticalcomposition examples.

PHARMACEUTICAL DOSAGE FORM EXAMPLES EXAMPLE A

    ______________________________________                                        Tablets                                                                       No.   Ingredient       mg/tablet  mg/tablet                                   ______________________________________                                        1.    Active Compound  100        500                                         2.    Lactose USP      122        113                                         3.    Corn Starch, Food Grade,                                                                        30         40                                               as a 10% paste in                                                             Purified Water                                                          4.    Corn Starch, Food Grade                                                                         45         40                                         5.    Magnesium Stearate                                                                              3          7                                                Total            300        700                                         ______________________________________                                    

METHOD OF MANUFACTURE

Mix item nos. 1 and 2 in a suitable mixer for 10-15 minutes. Granulatethe mixture with item no. 3. Mill the damp granules through a coarsescreen (e.g., 1/4") if needed. Dry the damp granules. Screen the driedgranules if needed and mix with item no. 4 and mix for 10-15 minutes.Add item no. 5 and mix for 1-3 minutes. Compress the mixture toappropriate size and weight on a suitable tablet machine.

EXAMPLE B

    ______________________________________                                        Capsules                                                                      No.   Ingredient       mg/capsule mg/capsule                                  ______________________________________                                        1.    Active Compound  100        500                                         2.    Lactose USP      106        123                                         3.    Corn Starch, Food Grade,                                                                        40         70                                         4.    Magnesium Stearate NF                                                                           4          7                                                Total            250        700                                         ______________________________________                                    

METHOD OF MANUFACTURE

Mix item nos. 1, 2 and 3 in a suitable blender for 10-15 minutes. Additem no. 4 and mix for 1-3 minutes. Fill the mixture into suitabletwo-piece hard gelatin capsules on a suitable encapsulating machine.

While the present invention has been described in connection withcertain specific embodiments thereof, it will be evident to one ofordinary skill in the art that many alternatives, modifications andvariations may be made. All such alternatives, modifications andvariations are intended to be included within the spirit and scope ofthe invention.

We claim:
 1. A compound having thename:1-(4-pyridinylcarbonyl)-4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta-[1,2-b]pyridin-11-ylidene)piperidine,i.e.,##STR167##1-(2-pyridinylcarbonyl)-4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta-[1,2-b]pyridin-11-ylidene)piperidine;1-(3-pyridinylcarbonyl)-4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta-[1,2-b]pyridin-11-ylidene)piperidine;1-(2-pyrazinylcarbonyl)-4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)piperidine;or1-(4-pyridazinylcarbonyl)-4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)piperidine.2. A pharmaceutical composition comprising a compound as defined inclaim 1 in combination with a pharmaceutically acceptable carrier.
 3. Amethod of treating allergy comprising administering a compound asdefined in claim 1 to a mammal in need of such treatment in an amounteffective to treat allergy.
 4. A method of treating inflammationcomprising administering to a mammal in need of such treatment anantiinflammatory effective amount of a compound as defined in claim 1.5. A compound having thename:1-(4-pyridinylcarbonyl)-4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta-[1,2-b]pyridin-11-ylidene)piperidine,i.e., ##STR168##
 6. A pharmaceutical composition comprising a compoundas defined in claim 5 in combination with a pharmaceutically acceptablecarrier.
 7. A method of treating allergy comprising administering acompound as defined in claim 5 to a mammal in need of such treatment inan amount effective to treat allergy.
 8. A method of treatinginflammation comprising administering to a mammal in need of suchtreatment an antiinflammatory effective amount of a compound as definedin claim 5.